Chemical Compounds

ABSTRACT

The present disclosure concerns compounds of Formula (I) 
     
       
         
         
             
             
         
       
     
     or pharmaceutically-acceptable salts thereof, wherein R 1 , R 2  and R 3  have any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of cancer.

This application claims the benefit under 35 U.S.C. §119(e) ofApplication No. 62/252,726 filed on 9 Nov. 2015 and Application No.62/401,351 filed on 29 Sep. 2016.

The present disclosure relates to certain dihydroimidazopyrazinonederivatives and pharmaceutically-acceptable salts thereof thatselectively inhibit ERK and possess anti-cancer activity. The presentdisclosure also relates to use of said dihydroimidazopyrazinonederivatives and pharmaceutically-acceptable salts thereof in methods oftreatment of the human or animal body, for example in prevention ortreatment of cancer. The present disclosure also relates to processesand intermediate compounds involved in the preparation of saiddihydroimidazopyrazinone derivatives and to pharmaceutical compositionscontaining said dihydroimidazopyrazinone derivatives andpharmaceutically-acceptable salts thereof.

Protein kinases play a key regulatory role in almost every aspect ofcell biology. The mammalian MAP kinases consist of cytoplasmic proteinserine/threonine kinases that participate in the transduction ofcellular signals from the plasma membrane to the nucleus. There aremultiple MAPK signalling cascades each consisting of 3 components: aMAPK kinase (MAP3K), a MAPK kinase (MAP2K) and a MAPK. The activated MAPkinases phosphorylate numerous substrates including other proteinkinases, protein phosphatases, transcription factors and otherfunctional proteins. The RAS-RAF-MEK-ERK signalling cascade participatesin the regulation of cell cycle progression, cell proliferation,survival, metabolism and transcription.

ERK1 and ERK2 are ubiquitously expressed MAPK kinases that participatein the RAS-RAF-MEK-ERK signalling cascade, which both contain unique N-and C-terminal extensions that provide signalling specificity, inaddition to a 31-amino-acid-residue insertion within the kinase domainthat provide additional functional specificity. ERK1 and ERK2 areactivated in a wide variety of cell types by mitogenic and otherstimuli, resulting in activation of multiple isoforms of RAS (HRAS, NRASand KRAS). Activation of RAS leads to recruitment and activation of RAFisoforms (ARAF, BRAF and CRAF) and subsequent activation of MEK1 andMEK2, dual-specificity protein kinases that mediate the phosphorylationof tyrosine and threonine of ERK1 and ERK2. ERK1 and ERK2 have a largenumber of identified cytoplasmic and nuclear substrates (reference YoonS, Seger R. The extracellular signal-regulated kinase: multiplesubstrates regulate diverse cellular functions; Growth Factors 2006, 24,21-44).

The RAS-RAF-MEK-ERK signalling cascade is deregulated in a variety ofdiseases including brain injury, cancer, cardiac hypertrophy, diabetesand inflammation.

Specifically in cancer, mutations in KRAS occur in approximately 58% ofpancreatic, 33% of colorectal and 31% of biliary cancers, and NRASmutations in 18% of melanomas.

Oncogenic mutations in RAS result in elevated ERK activity acrossmultiple tumours. In addition, BRAF mutations occur in approximately40-60% of melanomas, 40% of thyroid cancers and 20% of colorectalcancers (reference Vakiani E, Solit D B. KRAS and BRAF; drug targets andpredictive biomarkers; Journal of Pathology 2011, 223, 219-29). Theseobservations indicate that the RAS-RAF-MEK-ERK signalling cascade is anattractive pathway for anti-cancer therapies across a broad range ofhuman tumours.

We have found a series of chemical compounds which have selectivity forinhibition of ERK over other kinases on the same signalling cascade.

Where inhibition of ERK is referred to herein, it should be understoodto mean inhibition of ERK1 and/or ERK2, particularly ERK2.

According to one aspect there is provided a compound of the Formula (I):

wherein:R¹ is hydrogen, C₁₋₃ alkyl or —CH₂OMe;R² is pyridinyl, optionally substituted on 1 ring carbon atom by asubstituent independently selected from the group consisting of C₁₋₃alkyl, difluoromethyl and trifluoromethyl; orR² is pyrimidinyl, optionally substituted on 1 ring carbon atom by asubstituent independently selected from the group consisting of C₁₋₃alkyl, difluoromethyl and trifluoromethyl; orR² is phenyl optionally substituted on 1 or 2 ring carbon atoms by asubstituent independently selected from the group consisting of halo,difluoromethyl, trifluoromethyl, methoxy and —OCHF₂; andR³ is hydrogen, C₁₋₃ alkyl or chloro;or a pharmaceutically-acceptable salt thereof.

In one embodiment there is provided a compound of Formula (I) as definedabove.

In one embodiment there is provided a pharmaceutically-acceptable saltof a compound of Formula (I).

The term “optionally substituted” will be understood to mean“substituted or unsubstituted”.

As used herein the term “alkyl” refers to both straight and branchedchain saturated hydrocarbon radicals having the specified number ofcarbon atoms. References to individual alkyl groups such as “propyl” arespecific for the straight chain version only and references toindividual branched chain alkyl groups such as ‘isopropyl’ are specificfor the branched chain version only.

Examples of C₁₋₃alkyl are methyl, ethyl, propyl and isopropyl.

Examples of C₁₋₄ alkyl include methyl, ethyl, propyl, isopropyl, butyland tert-butyl.

The terms “halogen” or “halo,” as used herein, refers to fluoro, chloro,bromo and iodo. In certain embodiments, the term “halo” may refer tofluoro, chloro, and bromo. In certain embodiments, the term “halo” mayrefer to fluoro and chloro. In certain embodiments, the term “halo” mayrefer to fluoro. In certain embodiments, the term “halo” may refer tochloro. In certain embodiments, the term “halo” may refer to bromo.

In one aspect R¹ is hydrogen, methyl or —CH₂OMe.

In one aspect R¹ is methyl or —CH₂OMe.

In one aspect, R¹ is hydrogen.

In one aspect, R¹ is methyl.

In one aspect, R¹ is —CH₂OMe.

In one aspect, R² is pyridinyl, optionally substituted on 1 ring carbonatom by a substituent independently selected from the group consistingof methyl, difluoromethyl and trifluoromethyl; or

R² is pyrimidinyl, optionally substituted on 1 ring carbon atom by asubstituent independently selected from the group consisting of methyl,difluoromethyl and trifluoromethyl; orR² is phenyl optionally substituted on 1 or 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoro,chloro, difluoromethyl, trifluoromethyl, methoxy and —OCHF₂.

In one aspect, R² is pyridinyl, optionally substituted on 1 ring carbonatom by a substituent independently selected from the group consistingof methyl, difluoromethyl and trifluoromethyl; or

R² is pyrimidinyl, optionally substituted on 1 ring carbon atom bytrifluoromethyl; orR² is phenyl optionally substituted on 1 or 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoro,chloro, difluoromethyl, trifluoromethyl, methoxy and —OCHF₂.

In one aspect, R² is pyridinyl, optionally substituted on 1 ring carbonatom by a substituent independently selected from the group consistingof methyl, difluoromethyl and trifluoromethyl; or

R² is pyrimidinyl, optionally substituted on 1 ring carbon atom bytrifluoromethyl; orR² is phenyl optionally substituted on 1 ring carbon atom by asubstituent independently selected from the group consisting fluoro,chloro, difluoromethyl, trifluoromethyl, methoxy and —OCHF₂.

In one aspect, R² is pyridinyl, optionally substituted on 1 ring carbonatom by a substituent independently selected from the group consistingof methyl, difluoromethyl and trifluoromethyl; or

R² is pyrimidinyl, optionally substituted on 1 ring carbon atom bytrifluoromethyl; orR² is phenyl optionally substituted on 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoro,chloro, difluoromethyl, trifluoromethyl, methoxy and —OCHF₂.

In one aspect, R² is pyridinyl, optionally substituted on 1 ring carbonatom by a substituent independently selected from the group consistingof methyl, difluoromethyl and trifluoromethyl; or

R² is pyrimidinyl, optionally substituted on 1 ring carbon atom bytrifluoromethyl; orR² is phenyl optionally substituted on 1 or 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoro,chloro, difluoromethyl, methoxy and —OCHF₂.

In one aspect, R² is pyridinyl, optionally substituted on 1 ring carbonatom by difluoromethyl; or

R² is phenyl optionally substituted on 1 or 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoroand chloro.

In one aspect, R² is pyridinyl, optionally substituted on 1 ring carbonatom by a substituent independently selected from the group consistingof methyl, difluoromethyl and trifluoromethyl.

In one aspect, R² is pyridinyl, optionally substituted on 1 ring carbonatom by a methyl.

In one aspect, R² is pyridinyl, optionally substituted on 1 ring carbonatom by difluoromethyl.

In one aspect, R² is pyridinyl, optionally substituted on 1 ring carbonatom by trifluoromethyl.

In one aspect, R² is pyrimidinyl, optionally substituted on 1 ringcarbon atom by a substituent independently selected from the groupconsisting of methyl, difluoromethyl or trifluoromethyl.

In one aspect, R² is pyrimidinyl, optionally substituted on 1 ringcarbon atom by methyl.

In one aspect, R² is pyrimidinyl, optionally substituted on 1 ringcarbon atom by difluoromethyl.

In one aspect, R² is pyrimidinyl, optionally substituted on 1 ringcarbon atom by trifluoromethyl.

In one aspect, R² is phenyl optionally substituted on 1 or 2 ring carbonatoms by a substituent independently selected from the group consistingof fluoro, chloro, difluoromethyl, trifluoromethyl, methoxy and —OCHF₂.

In one aspect, R² is phenyl optionally substituted on 1 or 2 ring carbonatoms by a substituent independently selected from the group consistingof fluoro, chloro, difluoromethyl, methoxy and —OCHF₂.

In one aspect, R² is phenyl optionally substituted on 1 or 2 ring carbonatoms by a substituent independently selected from fluoro, chloro ormethoxy.

In one aspect, R² is phenyl optionally substituted on 2 ring carbonatoms by a substituent independently selected from the group consistingof fluoro, chloro and methoxy.

In one aspect, R² is phenyl optionally substituted on 1 or 2 ring carbonatoms by a substituent independently selected from the group consistingfluoro, chloro and methoxy.

In one aspect, R² is phenyl optionally substituted on 1 or 2 ring carbonatoms by a substituent independently selected from the group consistingfluoro and chloro.

In one aspect, R² is phenyl optionally substituted on 1 ring carbon atomby a substituent independently selected from the group consisting offluoro and chloro.

In one aspect, R² is phenyl optionally substituted on 2 ring carbonatoms by a substituent independently selected from the group consistingof fluoro and chloro.

In one aspect, R² is phenyl optionally substituted on 1 or 2 ring carbonatoms by a substituent independently selected from the group consistingfluoro and methoxy.

In one aspect, R² is phenyl optionally substituted on 2 ring carbonatoms by a substituent independently selected from the group consistingof fluoro and methoxy.

In one aspect, R² is phenyl optionally substituted on 1 or 2 ring carbonatoms by fluoro.

In one aspect, R² is phenyl optionally substituted on 1 or 2 ring carbonatoms by chloro.

In one aspect, R² is phenyl optionally substituted on 1 or 2 ring carbonatoms by difluoromethyl.

In one aspect, R² is phenyl optionally substituted on 1 or 2 ring carbonatoms by trifluoromethyl.

In one aspect, R² is phenyl optionally substituted on 1 or 2 ring carbonatoms by methoxy.

In one aspect, R² is phenyl optionally substituted on 1 or 2 ring carbonatoms by —OCHF₂.

In one aspect, R² is phenyl optionally substituted on 2 ring carbonatoms by fluoro.

In one aspect, R² is phenyl optionally substituted on 1 ring carbon atomby chloro.

In one aspect, R² is 6-methylpyridin-2-yl,4-(difluoromethyl)pyridin-2-yl, 6-(difluoromethyl)pyridin-2-yl,4-(trifluoromethyl)pyridin-2-yl, 6-(trifluoromethyl)pyridin-2-yl,2-(trifluoromethyl)pyridin-4-yl, 2-(trifluoromethyl)pyrimidin-4-yl,6-(trifluoromethyl)pyrimidin-4-yl, 3-chlorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 3-(difluoromethoxy)phenyl,3-(difluoromethyl)phenyl, 3-methoxyphenyl or 4-fluoro-3-methoxyphenyl.

In one aspect, R² is 6-(difluoromethyl)pyridin-2-yl, 3-chlorophenyl,3,4-difluorophenyl or 3,5-difluorophenyl.

In one aspect, R² is 6-methylpyridin-2-yl.

In one aspect, R² is 4-(difluoromethyl)pyridin-2-yl.

In one aspect, R² is 6-(difluoromethyl)pyridin-2-yl.

In one aspect, R² is 4-(trifluoromethyl)pyridin-2-yl.

In one aspect, R² is 6-(trifluoromethyl)pyridin-2-yl.

In one aspect, R² is 2-(trifluoromethyl)pyridin-4-yl.

In one aspect, R² is 2-(trifluoromethyl)pyrimidin-4-yl.

In one aspect, R² is 6-(trifluoromethyl)pyrimidin-4-yl.

In one aspect, R² is 3-chlorophenyl.

In one aspect, R² is 3,4-difluorophenyl.

In one aspect, R² is 3,5-difluorophenyl.

In one aspect, R² is 3-chloro-4-fluorophenyl.

In one aspect, R² is 3-(difluoromethoxy)phenyl.

In one aspect, R² is 3-(difluoromethyl)phenyl.

In one aspect, R² is 3-methoxyphenyl.

In one aspect, R² is 4-fluoro-3-methoxyphenyl.

In one aspect, R³ is hydrogen, methyl or chloro.

In one aspect, R³ is hydrogen or methyl.

In one aspect, R³ is hydrogen.

In one aspect, R³ is methyl.

In one aspect, R³ is chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is pyridinyl, optionally substituted on 1 ring carbon atom by asubstituent independently selected from the group consisting of methyl,difluoromethyl and trifluoromethyl; orR² is pyrimidinyl, optionally substituted on 1 ring carbon atom by asubstituent independently selected from the group consisting of methyl,difluoromethyl and trifluoromethyl; orR² is phenyl optionally substituted on 1 or 2 ring carbon atoms by asubstituent independently selected from the group consisting fluoro,chloro, difluoromethyl, trifluoromethyl, methoxy and —OCHF₂; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is pyridinyl, optionally substituted on 1 ring carbon atom by asubstituent independently selected from the group consisting of methyl,difluoromethyl and trifluoromethyl; orR² is pyrimidinyl, optionally substituted on 1 ring carbon atom bytrifluoromethyl; orR² is phenyl optionally substituted on 1 or 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoro,chloro, difluoromethyl, trifluoromethyl, methoxy and —OCHF₂; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is pyridinyl, optionally substituted on 1 ring carbon atom by asubstituent independently selected from the group consisting of methyl,difluoromethyl and trifluoromethyl; orR² is pyrimidinyl, optionally substituted on 1 ring carbon atom bytrifluoromethyl; orR² is phenyl optionally substituted on 1 carbon atom by a substituentindependently selected from the group consisting of fluoro, chloro,difluoromethyl, trifluoromethyl, methoxy and —OCHF₂; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is pyridinyl, optionally substituted on 1 ring carbon atom by asubstituent independently selected from the group consisting of methyl,difluoromethyl and trifluoromethyl; orR² is pyrimidinyl, optionally substituted on 1 ring carbon atom bytrifluoromethyl; orR² is phenyl optionally substituted on 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoro,chloro, difluoromethyl, trifluoromethyl, methoxy and —OCHF₂; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is pyridinyl, optionally substituted on 1 ring carbon atom by asubstituent independently selected from the group consisting of methyl,difluoromethyl and trifluoromethyl; orR² is pyrimidinyl, optionally substituted on 1 ring carbon atom bytrifluoromethyl; orR² is phenyl optionally substituted on 1 or 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoro,chloro, difluoromethyl, methoxy and —OCHF₂; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is methyl or —CH₂OMe;R² is pyridinyl, optionally substituted on 1 ring carbon atom bydifluoromethyl; orR² is phenyl optionally substituted on 1 or 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoroand chloro; andR³ is hydrogen or methyl.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is pyridinyl, optionally substituted on 1 ring carbon atom by asubstituent independently selected from the group consisting of methyl,difluoromethyl and trifluoromethyl; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is pyridinyl, optionally substituted on 1 ring carbon atom by methyl;andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is pyridinyl, optionally substituted on 1 ring carbon atom bydifluoromethyl; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is pyridinyl, optionally substituted on 1 ring carbon atom bytrifluoromethyl; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is pyrimidinyl, optionally substituted on 1 ring carbon atom bytrifluoromethyl; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is phenyl optionally substituted on 1 or 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoro,chloro, difluoromethyl, trifluoromethyl, methoxy and —OCHF₂; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is phenyl optionally substituted on 1 or 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoro,chloro, difluoromethyl, trifluoromethyl, methoxy and —OCHF₂; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is phenyl optionally substituted on 1 or 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoro,chloro, difluoromethyl and methoxy; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is phenyl optionally substituted on 1 or 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoro,chloro and methoxy; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is phenyl optionally substituted on 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoro,chloro and methoxy; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is phenyl optionally substituted on 1 or 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoroand chloro; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is phenyl optionally substituted on 1 or 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoroand methoxy; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is phenyl optionally substituted on 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoroand chloro; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is phenyl optionally substituted on 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoroand methoxy; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is 6-methylpyridin-2-yl, 4-(difluoromethyl)pyridin-2-yl,6-(difluoromethyl)pyridin-2-yl, 4-(trifluoromethyl)pyridin-2-yl,6-(trifluoromethyl)pyridin-2-yl, 2-(trifluoromethyl)pyridin-4-yl,2-(trifluoromethyl)pyrimidin-4-yl, 6-(trifluoromethyl)pyrimidin-4-yl,3-chlorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,3-chloro-4-fluorophenyl, 3-(difluoromethoxy)phenyl,3-(difluoromethyl)phenyl, 3-methoxyphenyl or 4-fluoro-3-methoxyphenyl;andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is 6-(difluoromethyl)pyridin-2-yl, 3-chlorophenyl, 3,4-difluorophenylor 3,5-difluorophenyl; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is methyl or —CH₂OMe;R² is 6-(difluoromethyl)pyridin-2-yl, 3-chlorophenyl, 3,4-difluorophenylor 3,5-difluorophenyl; andR³ is hydrogen or methyl.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is 6-(difluoromethyl)pyridin-2-yl; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is 3-chlorophenyl; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is 3,4-difluorophenyl; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is hydrogen, methyl or —CH₂OMe;R² is 3,5-difluorophenyl; andR³ is hydrogen, methyl or chloro.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is methyl or —CH₂OMe;R² is 6-(difluoromethyl)pyridin-2-yl; andR³ is hydrogen or methyl.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is methyl or —CH₂OMe;R² is 3-chlorophenyl; andR³ is hydrogen or methyl.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is methyl or —CH₂OMe;R² is 3,4-difluorophenyl; and R³ is hydrogen or methyl.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically-acceptable salt thereof, wherein:

R¹ is methyl or —CH₂OMe;R² is 3,5-difluorophenyl; andR³ is hydrogen or methyl.

In a further aspect, there is provided any one or more of the specificexamples or a pharmaceutically-acceptable salt thereof. In a furtheraspect, there is provided the specific examples described herein or apharmaceutically-acceptable salt thereof, wherein any one or more of theexamples is excluded. In a further aspect, there is provided a compoundselected from:

-   2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-methylpyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3-chlorobenzyl)-6-methyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3-chloro-4-fluorobenzyl)-6-methyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3,4-difluorobenzyl)-6-methyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   2-(5-Methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-(3-methoxybenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6-methyl-7-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6-methyl-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6-methyl-7-((6-methylpyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   7-(3-chloro-4-fluorobenzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   7-(3-chlorobenzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   7-(3-(difluoromethyl)benzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   7-((6-(difluoromethyl)pyridin-2-yl)methyl)-2-(5-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-(3-chlorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3-chlorobenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3,4-difluorobenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3-(difluoromethyl)benzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3,5-difluorobenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3-methoxybenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(4-fluoro-3-methoxybenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3-(difluoromethoxy)benzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((4-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((2-(trifluoromethyl)pyridin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-((4-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   7-(3,4-Difluorobenzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-6-Methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-((6-(Difluoromethyl)pyridin-2-yl)methyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-(3-(difluoromethyl)benzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-6-(Methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-(3,5-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;    and-   (R)-7-(3-Methoxybenzyl)-6-(methoxymethyl)-2-(5-methyl-2e    1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   or a pharmaceutically-acceptable salt thereof.

In a further aspect, there is provided a compound selected from:

-   (R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one    Ethanesulfonic acid adduct; and-   (R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one    Adipic acid adduct.

In a further aspect, there is provided a compound selected from:

-   (S)-7-(3-chlorobenzyl)-6-methyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2e    1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3,5-difluorobenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;    and-   (S)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   or a pharmaceutically-acceptable salt thereof.

In a further aspect, there is provided(S)-7-(3-chlorobenzyl)-6-methyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;or a pharmaceutically-acceptable salt thereof.

In a further aspect, there is provided(R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;or a pharmaceutically-acceptable salt thereof.

In a further aspect, there is provided(S)-7-(3,5-difluorobenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneor a pharmaceutically-acceptable salt thereof.

In a further aspect, there is provided(S)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;or a pharmaceutically-acceptable salt thereof.

In a further aspect there is provided the compound of Example 18 or apharmaceutically-acceptable adduct thereof.

Some compounds of Formula (I) have a chiral centre and it will berecognised that such compound of Formula (I) may be prepared, isolatedand/or supplied with or without the presence, in addition, of one ormore of the other 2 possible enantiomeric isomers of the compound ofFormula (I) in any relative proportions. The preparation ofenantioenriched/enantiopure compounds may be carried out by standardtechniques of organic chemistry that are well known in the art, forexample by synthesis from enantioenriched or enantiopure startingmaterials, use of an appropriate enantioenriched or enantiopure catalystduring synthesis, and/or by resolution of a racemic or partiallyenriched mixture of stereoisomers, for example via chiralchromatography.

For use in a pharmaceutical context it may be preferable to provide thecompound of Formula (I) or pharmaceutically-acceptable salt thereofwithout large amounts of the other stereoisomeric forms being present.

Accordingly, in one embodiment there is provided a compositioncomprising a compound of Formula (I) or a pharmaceutically-acceptablesalt thereof, optionally together with one or more of the otherstereoisomeric forms of the compound of Formula (I) orpharmaceutically-acceptable salt thereof, wherein the compound ofFormula (I) or pharmaceutically-acceptable salt thereof is presentwithin the composition with an enantiomeric excess (% ee) of >90%.

In a further embodiment the % ee in the above-mentioned composition is>95%.

In a further embodiment the % ee in the above-mentioned composition is>98%.

In a further embodiment the % ee in the above-mentioned composition is>99%.

In a further embodiment there is provided a pharmaceutical compositionwhich comprises a compound of the Formula (I) or apharmaceutically-acceptable salt thereof, in association with apharmaceutically-acceptable diluent or carrier.

In one embodiment there is provided a pharmaceutical composition whichcomprises a compound of the Formula (I) or a pharmaceutically-acceptablesalt thereof, in association with a pharmaceutically-acceptable diluentor carrier, optionally further comprising one or more of the otherstereoisomeric forms of the compound of Formula (I) orpharmaceutically-acceptable salt thereof, wherein the compound ofFormula (I) or pharmaceutically-acceptable salt thereof is presentwithin the composition with an enantiomeric excess (% ee) of >90%.

In a further embodiment the % ee in the above-mentioned composition is>95%.

In a further embodiment the % ee in the above-mentioned composition is>98%.

In a further embodiment the % ee in the above-mentioned composition is>99%.

The compounds of Formula (I) and pharmaceutically-acceptable saltsthereof may prepared, used or supplied in amorphous form, crystallineform, or semicrystalline form and any given compound of Formula (I) orpharmaceutically-acceptable salt thereof may be capable of being formedinto more than one crystalline/polymorphic form, including hydrated(e.g. hemi-hydrate, a mono-hydrate, a di-hydrate, a tri-hydrate or otherstoichiometry of hydrate) and/or solvated forms. It is to be understoodthat the present disclosure encompasses any and all such solid forms ofthe compound of Formula (I) and pharmaceutically-acceptable saltsthereof.

In further embodiments there is provided a compound of Formula (I),which is obtainable by the methods described in the ‘Examples’ sectionhereinafter.

The present disclosure is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes will be understood toinclude those atoms having the same atomic number but different massnumbers. For example, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include ¹³C and ¹⁴C.

A suitable pharmaceutically-acceptable salt of a compound of the Formula(I) is, for example, an acid addition salt.

A further suitable pharmaceutically-acceptable salt of a compound of theFormula (I) is, for example, a salt formed within the human or animalbody after administration of a compound of the Formula (I) to said humanor animal body.

A suitable pharmaceutically-acceptable salt of a compound of the Formula(I) may also be, for example, an acid-addition salt of a compound of theFormula (I), for example an acid-addition salt with a inorganic ororganic acid such as hydrochloric acid, hydrobromic acid, sulphuric acidor trifluoroacetic acid. Pharmaceutically-acceptable salts of a compoundof the Formula (I) may also be an acid-addition salt with an acid suchas one of the following: acetic acid, adipic acid, benzene sulfonicacid, benzoic acid, cinnamic acid, citric acid, D,L-lactic acid, ethanedisulfonic acid, ethane sulfonic acid, fumaric acid, L-tartaric acid,maleic acid, malic acid, malonic acid, methane sulfonic acid,napadisylic acid, phosphoric acid, saccharin, succinic acid or toluenesulfonic acid (such as p-toluenesulfonic acid). It is to be understoodthat a pharmaceutically-acceptable salt of a compound of the Formula (I)form an aspect of the present disclosure.

The compound of Formula (I) may be prepared as a co-crystal solid form.For the avoidance of doubt, a co-crystal refers to solids that arecrystalline single-phase materials composed of a compound of Formula (I)and at least one other molecular and/or ionic compound, herein referredto as a co-former, generally in a stoichiometric ratio, which areneither solvates nor simple salts. Generally speaking, if the compoundof Formula (I) and its coformer have a ΔpKa (pKa (base)−pKa (acid))>1,there will be substantial proton transfer resulting in ionization andpotential formation of a salt as opposed to a co-crystal. On the otherhand, if the compound of Formula (I) and its co-former have a ΔpKa (pKa(base)−pKa (acid))<1, there will be less than substantial protontransfer. If this criterion is met, the compound-co-former entity shouldbe classified as a co-crystal. In a co-crystal, the compound andco-former molecules interact by hydrogen bonding and possibly othernon-covalent interactions. It may be noted that a co-crystal may itselfform solvates, including hydrates.

Pharmaceutically-acceptable co-crystals of a compound of the Formula (I)may be, for example, adipic acid or fumaric acid co-crystals. It is tobe understood that a pharmaceutically-acceptable co-crystal of acompound of the Formula (I) forms another aspect of the presentdisclosure.

It is to be understood that the term “adduct”, as herein described,covers both pharmaceutically-acceptable salts andpharmaceutically-acceptable co-crystals of a compound of the Formula(I). A skilled person would be able to determine whether a salt or aco-crystal is formed based on the difference in the pKa of the compoundand its co-former as described hereinabove. In one aspect, an adduct isa salt. In another aspect, an adduct is a co-crystal.

Generally, reference herein to “a pharmaceutically-acceptable salt of acompound of Formula (I)” (or one of more of the Examples) in anyembodiment or aspect is to be understood to include a compound ofFormula (I) (or any one or more of the Examples respectively) presentedas a pharmaceutically-acceptable co-crystal or more generally describedas a (pharmaceutically-acceptable) adduct, unless the context demandsotherwise.

The term “pharmaceutically-acceptable co-crystal of a compound ofFormula (I)” is to be understood to refer to a co-crystal formed betweenthe compound of Formula (I) and a pharmaceutically-acceptable counterion(co-former). Similarly, the term “pharmaceutically-acceptable adduct ofa compound of formula (I)” is to be understood to refer to an adduct(salt or co-crystal) formed between the compound of Formula (I) and apharmaceutically-acceptable counterion (co-former).

(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct, herein referred to as Form 1, ischaracterised in providing at least one of the following 20 valuesmeasured using CuKα radiation: 23.3 and 16.7.

(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct, Form 1, is characterised in providing anX-ray powder diffraction pattern, substantially as shown in FIG. 1. TenX-Ray powder diffraction peaks are shown in Table 1:

TABLE 1 Ten X-Ray Powder Diffraction peaks for (R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one Ethanesulfonic acid adduct Form 1Angle 2-Theta (2θ) Intensity % 23.3 100 16.7 72 21.6 67 13.6 67 7.3 4719.6 37 25.8 33 28.1 32 14.5 25 11.0 24

According to the present disclosure there is provided a crystalline formof(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct.

According to the present disclosure there is provided a crystallineform,(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct, Form 1, which has an X-ray powderdiffraction pattern with at least one specific peak at about2-theta=23.3°.

According to the present disclosure there is provided a crystallineform,(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct, Form 1, which has an X-ray powderdiffraction pattern with at least one specific peak at about2-theta=16.7°.

According to the present disclosure there is provided a crystallineform,(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct, Form 1, which has an X-ray powderdiffraction pattern with at least two specific peaks at about2-theta=23.3° and 16.7°.

According to the present disclosure there is provided a crystallineform,(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct, Form 1, which has an X-ray powderdiffraction pattern with specific peaks at about 2-theta=23.3, 16.7,21.6, 13.6, 7.3, 19.6, 25.8, 28.1, 14.5, 11.0°.

According to the present disclosure there is provided crystalline form,(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct, Form 1, which has an X-ray powderdiffraction pattern substantially the same as the X-ray powderdiffraction pattern shown in FIG. 1.

According to the present disclosure there is provided crystalline form,(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct, Form 1, which has an X-ray powderdiffraction pattern with at least one specific peak at 2-theta=23.3°plus or minus 0.2°2-theta.

According to the present disclosure there is provided a crystallineform,(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct, Form 1, which has an X-ray powderdiffraction pattern with at least one specific peak at 2-theta=16.7°plus or minus 0.2°2-theta.

According to the present disclosure there is provided a crystallineform,(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct, Form 1, which has an X-ray powderdiffraction pattern with at least two specific peaks at 2-theta=23.3°and 16.7° wherein said values may be plus or minus 0.2°2-theta.

According to the present disclosure there is provided a crystallineform,(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct, Form 1, which has an X-ray powderdiffraction pattern with specific peaks at 2-theta=23.3, 16.7, 21.6,13.6, 7.3, 19.6, 25.8, 28.1, 14.5, 11.0° wherein said values may be plusor minus 0.2°2-theta.

DSC analysis of(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct, Form 1, shows a melting endotherm with anonset of 203.8° C. and a peak at 204.6° C. (FIG. 2).

Thus DSC analysis shows(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct, Form 1, is a high melting solid with anonset of melting at about 203.8° C. and a peak at about 204.6° C.

(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct, herein referred to as Form 1, is characterised inproviding at least one of the following 20 values measured using CuKαradiation: 8.6 and 9.8.

(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct, Form 1, is characterised in providing an X-raypowder diffraction pattern, substantially as shown in FIG. 3. Ten X-Raypowder diffraction peaks are shown in Table 2:

TABLE 2 Ten X-Ray Powder Diffraction peaks for(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin- 8(5H)-oneAdipic acid adduct Form 1 Angle 2-Theta (2θ) Intensity % 8.6 100 9.8 5817.8 18 6.3 13 10.3 13 25.8 12 19.1 11 22.8 11 25.1 11 13.2 11

According to the present disclosure there is provided a crystalline formof(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct.

According to the present disclosure there is provided a crystallineform,(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct, Form 1, which has an X-ray powder diffractionpattern with at least one specific peak at about 2-theta=8.6°.

According to the present disclosure there is provided a crystallineform,(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct, Form 1, which has an X-ray powder diffractionpattern with at least one specific peak at about 2-theta=9.8°.

According to the present disclosure there is provided a crystallineform,(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct, Form 1, which has an X-ray powder diffractionpattern with at least two specific peaks at about 2-theta=8.6° and9.80°.

According to the present disclosure there is provided a crystallineform,(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct, Form 1, which has an X-ray powder diffractionpattern with specific peaks at about 2-theta=8.6, 9.8, 17.8, 6.3, 10.3,25.8, 19.1, 22.8, 25.1, 13.20°.

According to the present disclosure there is provided crystalline form,(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct, Form 1, which has an X-ray powder diffractionpattern substantially the same as the X-ray powder diffraction patternshown in FIG. 3.

According to the present disclosure there is provided crystalline form,(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct, Form 1, which has an X-ray powder diffractionpattern with at least one specific peak at 2-theta=8.6° plus or minus0.2°2-theta.

According to the present disclosure there is provided a crystallineform,(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct, Form 1, which has an X-ray powder diffractionpattern with at least one specific peak at 2-theta=9.8° plus or minus0.2°2-theta.

According to the present disclosure there is provided a crystallineform,(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct, Form 1, which has an X-ray powder diffractionpattern with at least two specific peaks at 2-theta=8.6° and 9.80wherein said values may be plus or minus 0.2°2-theta.

According to the present disclosure there is provided a crystallineform,(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct, Form 1, which has an X-ray powder diffractionpattern with specific peaks at 2-theta=8.6, 9.8, 17.8, 6.3, 10.3, 25.8,19.1, 22.8, 25.1, 13.20 wherein said values may be plus or minus0.2°2-theta.

DSC analysis of(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct, Form 1, shows a melting endotherm with an onset of185.4° C. and a peak at 186.2° C. (FIG. 4).

Thus DSC analysis shows(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct, Form 1, is a high melting solid with an onset of185.4° C. and a peak at 186.2° C.

When it is stated that the present disclosure relates to a crystallineform of(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct, Form 1, and/or a crystalline form of(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct, Form 1, the degree of crystallinity is convenientlygreater than about 60%, more conveniently greater than about 80%,preferably greater than about 90% and more preferably greater than about95%. Most preferably, the degree of crystallinity is greater than about98%.

The(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct, Form 1, provides X-ray powder diffractionpatterns substantially the same as the X-ray powder diffraction patternsshown in FIG. 1 and has the ten (angle 2-theta values) shown in Table 1.The(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct, Form 1, provides X-ray powder diffraction patternssubstantially the same as the X-ray powder diffraction patterns shown inFIG. 3 and has the ten (angle 2-theta values) shown in Table 2. It willbe understood that the 2-theta values of the X-ray powder diffractionpattern may vary slightly from one machine to another or from one sampleto another, and so the values quoted are not to be construed asabsolute.

It is known that an X-ray powder diffraction pattern may be obtainedwhich has one or more measurement errors depending on measurementconditions (such as equipment or machine used). In particular, it isgenerally known that intensities in an X-ray powder diffraction patternmay fluctuate depending on measurement conditions. Therefore it shouldbe understood that the(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct, Form 1, of the present disclosure is notlimited to the crystals that provide X-ray powder diffraction patternsidentical to the X-ray powder diffraction pattern shown in FIG. 1, andany crystals providing X-ray powder diffraction patterns substantiallythe same as those shown in FIG. 1 fall within the scope of the presentdisclosure. In addition, it should be understood that the(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct, Form 1, of the present disclosure is not limited tothe crystals that provide X-ray powder diffraction patterns identical tothe X-ray powder diffraction pattern shown in FIG. 3, and any crystalsproviding X-ray powder diffraction patterns substantially the same asthose shown in FIG. 3 fall within the scope of the present disclosure. Aperson skilled in the art of X-ray powder diffraction is able to judgethe substantial identity of X-ray powder diffraction patterns.

Persons skilled in the art of X-ray powder diffraction will understandthat the relative intensity of peaks can be affected by, for example,grains above 30 microns in size and non-unitary aspect ratios, which mayaffect analysis of samples. The skilled person will also understand thatthe position of reflections can be affected by the precise height atwhich the sample sits in the diffractometer and the zero calibration ofthe diffractometer. The surface planarity of the sample may also have asmall effect. Hence the diffraction pattern data presented are not to betaken as absolute values. (Jenkins, R & Snyder, R. L. ‘Introduction toX-Ray Powder Diffractometry’ John Wiley & Sons 1996; Bunn, C. W. (1948),Chemical Crystallography, Clarendon Press, London; Klug, H. P. &Alexander, L. E. (1974), X-Ray Diffraction Procedures).

Generally, a measurement error of a diffraction angle in an X-ray powderdiffractogram is approximately plus or minus 0.2°2-theta, and suchdegree of a measurement error should be taken into account whenconsidering the X-ray powder diffraction pattern in FIG. 1 and whenreading Table 1. Furthermore, it should be understood that intensitiesmight fluctuate depending on experimental conditions and samplepreparation (preferred orientation).

Any crystal form that provides a XRPD diffractogram or DSC thermogramsubstantially identical to those disclosed herein, fall within the scopeof the present disclosures. One skilled in the art will have the abilityto determine substantial identities of diffractograms, spectra andthermograms.

XRPD and DSC methodology conditions are herein described in theExamples.

It is to be understood that a suitable pharmaceutically-acceptablepro-drug of a compound of the Formula (I) also forms an aspect of thepresent disclosure. Accordingly, the compounds of the disclosure may beadministered in the form of a pro-drug, which is a compound that isbroken down in the human or animal body to release a compound of thedisclosure. A pro-drug may be used to alter the physical propertiesand/or the pharmacokinetic properties of a compound of the presentdisclosure. A pro-drug can be formed when the compound of the presentdisclosure contains a suitable group or substituent to which aproperty-modifying group can be attached. Examples of pro-drugs includein-vivo cleavable ester or amide derivatives that may be formed at thecarboxy group in a compound of the Formula (I).

Accordingly, one aspect of the present disclosure includes thosecompounds of Formula (I) as defined hereinbefore when made available byorganic synthesis and when made available within the human or animalbody by way of cleavage of a pro-drug thereof.

Accordingly, the present disclosure includes those compounds of theFormula (I) that are produced by organic synthetic means and also suchcompounds that are produced in the human or animal body by way ofmetabolism of a precursor compound, that is a compound of the Formula(I) may be a synthetically-produced compound or a metabolically-producedcompound.

A suitable pharmaceutically-acceptable pro-drug of a compound of theFormula (I) is one that is based on reasonable medical judgement asbeing suitable for administration to the human or animal body withoutundesirable pharmacological activities and without undue toxicity.

Various forms of pro-drug have been described, for example in thefollowing documents:—

-   a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder,    et al. (Academic Press, 1985);-   b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);-   c) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and    Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991);-   d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);-   e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285    (1988);-   f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);-   g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”,    A.C.S. Symposium Series, Volume 14; and-   h) E. Roche (editor), “Bioreversible Carriers in Drug Design”,    Pergamon Press, 1987.

A suitable pharmaceutically-acceptable pro-drug of a compound of theFormula (I) that possesses a carboxy group is, for example, an in-vivocleavable ester thereof. An in-vivo cleavable ester of a compound of theFormula (I) containing a carboxy group is, for example, apharmaceutically-acceptable ester which is cleaved in the human oranimal body to produce the parent acid. Suitablepharmaceutically-acceptable esters for a carboxy group include(1-6C)alkyl esters such as methyl, ethyl and tert-butyl,(1-6C)alkoxymethyl esters such as methoxymethyl esters,(1-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters,3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters suchas cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters,2-oxo-1,3-dioxolenylmethyl esters such as5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and(1-6C)alkoxycarbonyloxy-(1-6C)alkyl esters such asmethoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters.

A suitable pharmaceutically-acceptable pro-drug of a compound of theFormula (I) which have a carboxy group is for example an in-vivocleavable amide such as a N—C₁₋₆alkyl and N,N-di-(C₁₋₆alkyl)amide suchas N-methyl, N-ethyl, N-propyl, N,N-dimethyl, N-ethyl-N-methyl orN,N-diethylamide.

The in-vivo effects of a compound of the Formula (I) may be exerted inpart by one or more metabolites that are formed within the human oranimal body after administration of a compound of the Formula (I). Asstated hereinbefore, the in-vivo effects of a compound of the Formula(I) may also be exerted by way of metabolism of a precursor compound (apro-drug).

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘hereinbefore defined’ or ‘definedherein’ the said group encompasses the first occurring and broadestdefinition as well as each and all of the alternative definitions forthat group.

Another aspect of the present disclosure provides a process forpreparing a compound of the Formula (I), or apharmaceutically-acceptable salt thereof. A suitable process isillustrated by the following representative process variants in which,unless otherwise stated R¹ to R³ has any of the meanings definedhereinbefore. Necessary starting materials may be obtained by standardprocedures of organic chemistry or are commercially available. Thepreparation of such starting materials is described in conjunction withthe following representative process variants and within theaccompanying Examples. Alternatively, necessary starting materials areobtainable by analogous procedures to those illustrated which are withinthe ordinary skill of an organic chemist.

A compound of formula (I) may be prepared from a compound of formula(II), wherein L¹ is a suitable leaving group (such as halogen, or—SO₂Me, etc), by reaction with a compound of formula (XII), wherein P¹is hydrogen, with a suitable base (such as NaH, Na₂CO₃, Cs₂CO₃ or K₂CO₃)in a suitable solvent (such as N,N-dimethylformamide orN,N-dimethylacetamide) or in the presence of a suitable Pd catalyst andphosphine ligand with a suitable base (e.g. Cs₂CO₃) in a suitablesolvent (such as dioxane), under conditions of ambient or elevatedtemperatures (such as achieved by heating or by microwave irradiation).Alternatively, a compound of formula (I) may be prepared from a compoundof formula (II), wherein L¹ is a suitable leaving group (such as halo,or —SO₂Me, etc.), by reaction with a compound of formula (XII), whereinP¹ is a suitable group other than hydrogen (such as formyl ortrifluoroacetamide) with a suitable base (such as NaH, Na₂CO₃, Cs₂CO₃ orK₂CO₃) in a suitable solvent (such as N,N-dimethylformamide orN,N-dimethylacetamide) or in the presence of a suitable Pd catalyst andphosphine ligand with a suitable base (e.g. Cs₂CO₃) in a suitablesolvent (such as dioxane), under conditions of elevated temperatures(such as achieved by heating or by microwave irradiation), followed byremoval of the protecting group P¹ in the presence of a suitable basesuch as sodium hydroxide in a suitable solvent and water.

It will be appreciated that a compound of formula (I) may be transformedinto another compound of formula (I) using conditions well known in theart.

Compounds of formula (XII) are either commercially available or wellknown in the art.

A compound of formula (II) may be prepared from a compound of formula(III), wherein L¹ is a suitable leaving group (such as Cl or —SO₂Me), byreaction with a compound of formula (XIII) wherein L² is a suitableleaving group (such as halogen, or —OSO₂Me, -Tos, etc), in the presenceof a suitable base (such as sodium hydride or K₂CO₃) and a suitablesolvent (such as N,N-dimethylformamide).

Compounds of formula (XIII) are either commercially available or wellknown in the art.

Alternatively compounds of formula (II) may be prepared from compoundsof formula (VI), wherein R⁴ is an alkyl group (such as methyl or ethyl),by the reaction with compounds of the formula (X) in the presence ofsuitable reducing reagent (such as NaBH₃CN) and a suitable solvent (suchas tetrahydrofuran) followed by subsequent lactamisation conditions in asuitable solvent (such as MeOH) with a suitable base (such as ammonia),or with a Lewis acid catalyst (such as trimethylaluminium).

Compounds of formula (X) are either commercially available or well knownin the art.

A compound of formula (II) wherein L¹ is a pre-cursor to a suitableleaving group (such as —SMe, etc) may be prepared from a compound offormula (V), wherein L³ is a suitable metal group (such as trimethylstannane, etc), by reaction with a compound of formula (XI) wherein L²is a suitable leaving group (such as halo, or OSO₂CF₃), in the presenceof a suitable Pd catalyst and phosphine ligand in a suitable solvent(such as a mixture of N,N-dimethylformamide, dimethoxyethane, water andethanol) under suitable conditions such as heating thermally or in amicrowave reactor.

Compounds of formula (XI) are either commercially available or wellknown in the art.

A compound of formula (V), wherein R¹ is hydrogen or an alkyl group(such as methyl), may be prepared from a compound of formula (VII), byreaction with a compound of formula (XIV) where L⁴ is a suitable leavinggroup (such as halo, or OSO₂CF₃), in the presence of a suitable base(such as sodium hydride or K₂CO₃) and a suitable solvent (such asN,N-dimethylformamide or acetone).

Compounds of formula (XIV) are either commercially available or wellknown in the art.

A compound of formula (VI), wherein R⁴ is an alkyl group (such as methylor ethyl), may be prepared from a compound of formula (VIII), byreaction with either a compound of formula (XV), wherein L⁵ is asuitable leaving group (such as halo, —OSO₂Me or —OSO₂CF₃) and P³ is asuitable protecting group (such as -Boc), or a compound of formula (XVI)wherein P³ is a suitable protecting group (such as -Boc), in thepresence of a suitable base (such as sodium hydride or K₂CO₃) in asuitable solvent (such as dioxane or MeCN) under conditions of ambientor elevated temperatures (such as achieved by heating or by microwaveirradiation); In the case where compound of formula (XVI) is used it maybe necessary to remove the intermediate sulfamic acid under conditionsof aqueous acid (such as HCl) in a suitable solvent (such as ethanol).The protecting group P³ can be removed from compounds of formula (XV)and (XVI) by the use of a suitable acid (such as HCl) in a suitablesolvent (such as dioxane or ethanol), under conditions of ambienttemperatures. A compound of formula (VI) may be isolated as a salt, suchas a hydrochloride or dihydrochloride salt.

Compounds of formula (XV) and (XVI) are either commercially available orwell known in the art.

The reaction of compound of formula (VIII) with a compound of formula(XVI) to prepare a compound of formula (VI) is novel and provides afurther aspect of this present disclosure.

Therefore in a further aspect, there is provided a process for preparinga compound of formula (VI), said process comprising:

-   -   a) reaction of a compound of formula (VIII) with a compound of        formula (XVI) in the presence of a suitable base in a suitable        solvent, under conditions of ambient or elevated temperatures;

wherein R¹ and R³ are defined for compound of formula (I) hereinbefore;L¹ is a leaving group or a pre-cursor to a leaving group;P³ is a protecting group; andR⁴ is an alkyl group; and

-   -   b) optionally, an intermediate sulfamic acid is removed under        conditions of aqueous acid in a suitable solvent; and    -   c) removal of the protecting group P³ in the presence of a        suitable acid in a suitable solvent, under ambient temperatures.

In one embodiment, L¹ is —SMe or halogen.

In one embodiment, L¹ is —SMe or Cl.

In one embodiment, R⁴ is an alkyl group.

In one embodiment, R⁴ is C₁₋₄ alkyl.

In one embodiment, R⁴ is methyl or ethyl.

In one embodiment, R⁴ is methyl.

In one embodiment, R⁴ is ethyl.

In one embodiment, a suitable base is sodium hydride or K₂CO₃.

In one embodiment, a suitable base is sodium hydride.

In one embodiment, reaction of a compound of formula (VIII) with acompound of formula (XVI) is performed in dioxane or MeCN.

In one embodiment, reaction of a compound of formula (VIII) with acompound of formula (XVI) is performed in dioxane.

In one embodiment, reaction of a compound of formula (VIII) with acompound of formula (XVI) is performed in MeCN.

In one embodiment, reaction of a compound of formula (VIII) with acompound of formula (XVI) is performed at temperatures at about 20° C.

In one embodiment, reaction of a compound of formula (VIII) with acompound of formula (XVI) is performed at temperatures of 18-25° C.

In one embodiment, reaction of a compound of formula (VIII) with acompound of formula (XVI) is performed at temperatures >20° C.

In one embodiment, reaction of a compound of formula (VIII) with acompound of formula (XVI) is performed at temperatures >50° C.

In one embodiment, reaction of a compound of formula (VIII) with acompound of formula (XVI) is performed at temperatures >80° C.

In one embodiment, reaction of a compound of formula (VIII) with acompound of formula (XVI) is performed at temperatures ≧85° C.

In one embodiment, reaction of a compound of formula (VIII) with acompound of formula (XVI) is performed at temperatures ≧85° C. and ≦10°C.

In one embodiment, reaction of a compound of formula (VIII) with acompound of formula (XVI) is performed at temperatures ≦100° C.

In one embodiment, reaction of a compound of formula (VIII) with acompound of formula (XVI) is performed at temperatures ≧80° C. and ≦110°C.

In one embodiment, reaction of a compound of formula (VIII) with acompound of formula (XVI) is performed at temperatures ≦110° C.

In one embodiment, a suitable aqueous acid is HCl.

In one embodiment, removal of intermediate sulfamic acid is performed inethanol.

In one embodiment, P³ is -Boc.

In one embodiment, a suitable base is K₂CO₃.

In one embodiment, a suitable acid is HCl.

In one embodiment, removal of the protecting group P³ is performed indioxane or ethanol.

In one embodiment, removal of the protecting group P³ is performed inethanol.

In one embodiment, removal of the protecting group P³ is performed indioxane.

In one embodiment, removal of the protecting group P³ is at temperaturesof 18-25° C.

In one embodiment, removal of the protecting group P³ is at temperaturesof 22-28° C.

In one embodiment, removal of the protecting group P³ is at temperaturesat about 20° C.

In one embodiment, removal of the protecting group P³ is at temperaturesat about 25° C.

A compound of formula (VIII) wherein L¹ is a suitable leaving group(such as halogen, or —SO₂Me, etc) may be prepared from a compound offormula (IX), wherein R⁴ is an alkyl group (such as methyl, etc) and P⁴is a protecting group (such as SEM) by reaction with a compound offormula (XVII) wherein L⁵ is a suitable leaving group (such as halo, orOSO₂CF₃), in the presence of a suitable Pd catalyst and phosphineligand, with a suitable base (such as caesium carbonate) in a suitablesolvent (such as a mixture of dioxane and water), under suitableconditions (such as heating thermally or in a microwave reactor).

Compound of formula IX can be prepared by methods well known in the art.

A compound of formula (III) may also be prepared from a compound offormula (VI) wherein R⁴ is an alkyl group (such as methyl or ethyl) bytreatment with a suitable base (such as ammonia) in a suitable solvent(such as MeOH).

When a pharmaceutically-acceptable salt of a compound of the Formula (I)is required it may be obtained by, for example, reaction of saidcompound with a suitable acid or suitable base.

When a pharmaceutically-acceptable pro-drug of a compound of the Formula(I) is required, it may be obtained using a conventional procedure. Forexample, an in-vivo cleavable ester of compound of the Formula (I) maybe obtained by, for example, reaction of a compound of the Formula (I)containing a carboxy group with a pharmaceutically-acceptable alcohol.Further information on pro-drugs has been provided hereinbefore.

It will also be appreciated that, in some of the reactions mentionedhereinbefore, it may be necessary or desirable to protect any sensitivegroups in the compounds. The instances where protection is necessary ordesirable, and suitable methods for protection, are known to thoseskilled in the art. Conventional protecting groups may be used inaccordance with standard practice (for illustration see T. W. Green,Protective Groups in Organic Synthesis, John Wiley and Sons, 1991).Thus, if reactants include groups such as amino, carboxy or hydroxy, itmay be desirable to protect the group in some of the reactions mentionedherein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as pall adium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

Certain of the intermediates (for example, compounds of the Formulae II,III, IV, V, VI and VII, particularly Formulae II and VI) defined hereinare novel and these are provided as a further features of the presentdisclosure.

Biological Assays

The following assays were used to measure the effects of the compoundsof the present disclosure.

Compound Handling

All compounds or DMSO (dimethyl sulphoxide) for the ERK2 MassSpectrometry and A375 phospho-p90RSK assays were dispensed from sourceplates containing compounds at 10 mM in 100% (v/v) DMSO or 100% DMSO,directly into assay plates using an Echo 555 Acoustic dispenser (LabcyteInc™). Depending on the assay, two separate plate preparations werefollowed. In Workflow A, 10 mM compound stocks were diluted 1:100 usinga fixed-tip 96-head Agilent VPrep liquid handler (Agilent Technologies,Santa Clara, Calif.) to give four intermediate dilutions (10 mM, 100 μM,1 μM, nM). In Workflow B, 10 mM compound stocks were diluted 1:10 usinga Tecan Freedom Evo (Tecan Group Ltd., Switzerland), and then 1:100using the Echo 555 and Labcyte LX to produce three intermediatedilutions across three Labcyte qualified source plates (1 mM, 10 μM, 100nM). These intermediate dilution plates were then used by the Echo 555to generate final assay-ready compound plates with a 12 point dose range(10, 3, 1, 0.25, 0.1, 0.03, 0.01, 0.0025, 0.001, 0.0003, 0.0001,0.000012 μM) in order to calculate compound IC₅₀s, with a total DMSOconcentration in the assay of 1%. For the ERK2 Mass Spectrometry assayWorkflow B was used. For the A375 phospho-p90RSK cell assay, theintermediate 1:100 dilution plate described in Workflow A was used bythe Echo to dispense compounds and DMSO directly into the cell plateswith a 12 point dose range (30, 10, 3.125, 1.25, 0.3, 0.1, 0.03125,0.0125, 0.003, 0.001, 0.0003125, 0.00003 μM) in order to calculatecompound IC₅₀'s, with a total DMSO concentration in the assay of 0.3%.

ERK2 Rapidfire Mass Spectrometry Inhibition of Catalysis Assay

MEK U911-activated ERK2 protein was expressed and purified in-house.Enzyme and substrate solutions were made up in assay buffer consistingof 50 mM Tris (pH 7.5), 10 mM MgCl2, 0.1 mM EGTA (ethylene glycoltetraacetic acid), 10 mM DTT (dithiothreitol) and 0.01% (v/v) CHAPS(3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate). 1.2 nM ERK2protein was prepared in assay buffer and 10 μl was dispensed into eachwell of a polypropylene, 384-well plate (#781201, Greiner) containingtest and reference control compounds. Following a 15 minutepre-incubation of enzyme and compound at room temperature, 10 μl ofsubstrate solution was added consisting of 16 μM Erktide(IPTTPITTTYFFFK, #61777, AnaSpec) and 120 μM ATP (adenosinetriphosphate) (measured Km) in assay buffer. The reaction was allowed toprogress for 20 minutes at room temperature before being quenched by theaddition of 80 μl 1% (v/v) formic acid. The assay plates were then runon the RapidFire Mass Spectrometry platform (Agilent) to measuresubstrate (unphosphorylated Erktide) and product (phosphorylatedErktide) levels. Data was analysed and IC50's (half maximal inhibitoryconcentration) were calculated using Genedata Screener® software.

A375 Phospho-p90RSK Cellular Assay

The phospho-p90RSK cell assay was performed in the A375 cell line, ahuman malignant melanoma which has a BRAF mutation up-regulating theMAPK pathway and, hence, elevated endogenous levels of phospho-ERK andphospho-p90RSK. A375 cells were cultured in cell media composed of DMEM(Dulbecco's modified Eagle's medium), 10% (v/v) Foetal Calf Serum and 1%(v/v) L-Glutamine. After harvesting, cells were dispensed into black,384-well Costar plates (#3712, Corning) to give 2400 cells per well in atotal volume of 40 μl cell media, and were incubated overnight at 37°C., 90% relative humidity and 5% CO₂ in a rotating incubator. Testcompounds and reference controls were dosed directly into the cellplates using a Labcyte Echo 555 acoustic dispenser. The cell plates werethen incubated for 2 hours at 37° C. before being fixed by the additionof 20 μl 12% formaldehyde in PBS/A (4% final concentration), followed bya 20 minute room temperature incubation, and then a 2× wash with 150 μlPBS/A (phosphate buffered saline containing albumin) using a BioTekELx405 platewasher. Cells were permeabilised with 20 μl 0.1% TritonX-100 in PBS/A for 20 minutes at room temperature, and then washed 1×with 100 μl PBS/A. Primary phospho-p90RSK (Thr359) (D1E9) rabbitmonoclonal antibody (#8753, Cell Signaling Technology) was diluted1:1000 in assay buffer (0.05% (v/v) Tween, 5% (v/v) Foetal Calf Serum,in PBS/A), 20 μl added per well, and plates were incubated at 4° C.overnight. Cell plates were washed 2× with 200 μl PBS/T (phosphatebuffered saline containing Tween-20), then 20 μl 1:500 dilution in assaybuffer of Alexa Fluor® 647 goat anti-rabbit IgG secondary antibody(#A31573, Molecular Probes, Life Technologies), with a 1:5000 dilutionof Hoechst 33342, was added per well. Following a 90 minute incubationat room temperature, plates were washed 2× with 200 μl PBS/T, and 40 μlPBS/A was added per well. Stained cell plates were covered with blacklid seals, and then read on a Cellomics ArrayScan™ VTI imaging platform(Thermo Scientific), using an XF53 filter with 10× objective, with a LEDlight source set-up to analyse nuclear staining with Hoechst 33342 (405nm) and secondary antibody staining of phospho-p90RSK (647 nm). Data wasanalysed and IC50's were calculated using Genedata Screener® software.

Compounds as claimed herein generally have enzyme activity in the aboveassay of <0.5 mM, such as <0.2 mM.

The following data were generated for the Examples (the data below maybe a result from a single experiment or an average of two or moreexperiments; variations from data presented in applications from whichthis application claims priority are due to further repetitions of thetest causing slight changes in average values):

ERK2 Mass Spectrometry p90RSK cell IC₅₀ Example Enzyme IC₅₀ (μM) (μM)  10.0174 17  2 0.0007 0.086  3 0.0005 0.081  4 0.0018 0.63  5 0.002 0.11 6 0.0006 0.025  7 0.0005 0.038  8 0.0011 0.21  9 0.0005 0.19 10 0.00110.055 11 0.0008 0.15 12 0.0006 0.003 13 0.0003 0.012 14 0.0003 0.024 150.0006 0.15 16 0.0011 0.12 17 0.0009 0.0052 18 0.0006 0.0057  18a 0.00060.0074 19 0.0005 0.0053 20 0.0004 0.038 21 0.0006 0.011 22 0.0008 0.01923 0.0006 0.04 24 0.0005 0.084 25 0.0007 0.13 26 0.0011 0.2 27 0.00080.077 28 0.0005 0.11 29 0.0009 0.13 30 0.0007 0.2 31 0.0008 0.14 320.0009 0.099 33 0.0008 0.031 35 — 0.093 36 0.0014 0.051 37 0.0007 0.06438 0.0007 0.008 39 0.0018 0.070 40 0.0011 0.032 41 0.0015 0.130

Compounds of examples 1, 2, 3, 4, 6, 7, 9, 10, 11, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27 and 28 have been shown to be at least 500fold more selective for ERK2 over MEK in the MEK AutophosphorylationADP-Glo Assay below.

MEK Autophosphorylation ADP-Glo Assay

Activated MEK protein was supplied by MRC-PPU (DU911, Dundee, UK) orexpressed and purified in-house. The MEK assay was performed with theADP-Glo™ Kinase Assay Kit (Promega, Madison, Wis., USA), in Greiner384-well white low volume plates. 2 μl of 6 nM activated MEK protein, inassay buffer consisting of 50 mM Tris (pH 7.5), 10 mM DTT, 0.1 mM EGTA,0.01% v/v Tween20 and 10 mM MgCl₂, was dispensed into each well of aplate containing test and reference control compounds. Following a 15minute pre-incubation of enzyme and compound at room temperature, 2 μlof substrate solution was added consisting of 2 μM ATP (K_(Mapp) ^(ATP))in assay buffer. The assay reaction was allowed to proceed for 90 min atroom temperature before stopping the reaction by the addition of 2 μl ofADP-Glo reagent. Plates were then covered and incubated for 40 min atroom temperature. 4 μl Kinase Detection Reagent was then added andplates were incubated for 30 min, before the luminescence signal wasread with a PHERAstar plate reader (BMG Labtech GmbH, Offenburg,Germany).

Combination Studies Materials and Methods

A549 is a human non small cell lung cancer line carrying an oncogenicmutation in the KRAS gene (G12S). Female nude mice (Harlan, UK) wereimplanted subcutaneously (s.c.) on the left flank, with 5×10⁶ A549 cells(ATCC) per mouse.

Tumour growth was monitored by twice weekly calliper measurement andvolumes calculated using elliptical formula (pi/6×width×width×length).Once tumours had reached a volume of ˜200-300 mm³ animals wererandomised into groups of 7-11 and were treated with a continuouscombination schedule of selumetinib (ARRY-142886) 25 mg/kg BiD andExample 18a 25 mg/kg QD (four hours after first selumetinib dose), bothwere dosed by peroral route. Tumour volumes were measured twice weeklyafter dosing commenced.

Selumetinib was formulated in HPMC/Tween (0.5% Methocel [hydroxypropylmethocellulose]/0.1% Polysorbate 80), the suspension was stirred overnight. Example 18a was formulated in 10% DMSO, 90% of a 40% kleptosesolution (Kleptose is sourced from Roquette—Pharma [Trademarked]Hydroxypropyl betacyclodextrin—suitable for in-vivo use andformulations).

Tumour Growth Inhibition by Example 18a in Combination with MEKInhibitor (Selumetinib)

Studies were performed in the A549 xenograft model. Selumetinib wasdosed twice daily (BiD) 8 hours apart and Example 18a was dosed oncedaily (QD) 4 hours after the first selumetinib dose. Both compounds weredosed continuously for 3 weeks. Both vehicles were dosed in the vehiclegroup. Both selumetinib and Example 18a reduced tumour growth relativeto vehicle only control (shown in FIG. 5). The combination ofselumetinib plus Example 18a resulted in a further reduction in tumourgrowth, with evidence of regression in some animals.

Combination Studies—Cell Growth Inhibition Cell Lines and Treatments

A549 is a human non small cell lung cancer line carrying an oncogenicmutation in the KRAS gene (G12S). H2122 is a human non small cell lungcancer line carrying an oncogenic mutation in the KRAS gene (G12C).H2009 is a human non small cell lung cancer line carrying an oncogenicmutation in the KRAS gene (G12A). Calu6 is a human non small cell lungcancer line carrying mutation in the KRAS (G13K) gene. All cell lineswere obtained from the American Type Culture Collection.

All cell line were maintained at 37° C. and 5% CO₂ in a humidifiedatmosphere and grown in RPMI-1640 growth media supplemented with 10% FBSand 2 mmol/L glutamine. The identity of all cell lines was confirmedusing short tandem repeat analysis as described previously (Davies B R,Greenwood H, Dudley P, et al: Preclinical pharmacology of AZD5363, aninhibitor of AKT: Pharmacodynamics, antitumor activity, and correlationof monotherapy activity with genetic background. Mol Cancer Ther11(4):873-87, 2012). Compounds were dissolved in DMSO to a concentrationof 10 mmol/L and stored under nitrogen.

Determination of Cell Growth

Cells were seeded in 384-well black, clear bottomed plates (GreinerBio-One, Stonehouse, UK), cultured for 18-24 hours and treated withincreasing concentrations of Example 18 and selumetinib (0-10 μmol/L) ina 6×6 dosing matrix. Cells were seeded at a concentration such thatcells in untreated wells were approximately 80% confluent at the end ofthe assay. After 3 days of treatment, live cell number was determinedusing a Sytox Green endpoint as described previously (“Davies B R,Greenwood H, Dudley P, et al: Preclinical pharmacology of AZD5363, aninhibitor of AKT: Pharmacodynamics, antitumor activity, and correlationof monotherapy activity with genetic background. Mol Cancer Ther11(4):873-87, 2012”). Briefly, Sytox Green nucleic acid dye (Invitrogen)diluted in TBS-EDTA buffer was added to cells at a final concentrationof 0.13 μmol/L and the number of dead cells detected using an AcumenExplorer (TTP Labtech, Melbourn, UK). Cells were then permeabilised bythe overnight addition of saponin (0.03% final concentration, diluted inTBS-EDTA buffer) and a total cell count measured. The live cell countwas then determined by subtracting the number of dead cells per wellfrom the total number of cells. Pre-dose measurements were made toindicate the number of live cells at the start of the experiment andthus an indication of whether the treatment regimen had resulted in celldeath. The data is presented as % growth using the NCI formulas asfollows;

{[(Ti−Tz)/(C−Tz)]×100}+100, for values for which Ti>/=Tz

{[(Ti−Tz)/Tz]×100}+100, for concentrations for which Ti<Tz

where, Tz represents the number of live cells at time zero, C representsthe control growth and Ti represents the number of live cells in thepresence of each drug regimen. This formula gives a percentage from 0%to 200%. Anti-proliferative effects are indicated by scores from 0% (noeffect on cell growth) to 100% (complete inhibition of cell growth);cell killing is indicated by scores from 100% (no cell killing) to 200%(killing of all cells).

Analysis of combination activity Combination activity (synergism),across the 6×6 dose matrix, was analysed in Genedata Screener12(Genedata, Basel, Switzerland) using the Loewe dose-additivity model asdescribed previously (Lehar J, Krueger A S, Avery W, et al: Synergisticdrug combinations tend to improve therapeutically relevant selectivity.Nat Biotechnol 27(7):659-66, 2009 and Rickles R J, Tam W F, Giordano TP, 3rd, et al: Adenosine A2A and beta-2 adrenergic receptor agonists:Novel selective and synergistic multiple myeloma targets discoveredthrough systematic combination screening. Mol Cancer Ther 11(7):1432-42,201229). This model of additivity provides a null-reference that ispredicted by the expected response if the two agents were the same drug.The 3-dimensional model surface, predicted from the two single-agentresponse curves, is subtracted from the experimentally-derived3-dimensional dose effect surface to generate a difference volume. Thisexcess matrix volume can be integrated to generate a synergy score. Asynergy score cutoff >5 was used to identify combinations of interest inthe initial high-throughput screen.

The results (shown in FIGS. 6-17) demonstrate that Example 18 caninhibit the growth of a panel of cancer cell lines with KRAS mutationsas a monotherapy and this effect is synergistically enhanced bytreatment with selumetinib. Synergy scores for each cell line are 25(A549), 14.3 (H2122), 67.5 (H2009), and 3 (Calu6). The synergy scoresabove are an average of three or more independent experiments.

According to a further aspect of the present disclosure there isprovided a pharmaceutical composition, which comprises a compound of theFormula (I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore in association with a pharmaceutically-acceptable diluentor carrier.

Suitable pharmaceutically-acceptable excipients for a tablet formulationinclude, for example, inert diluents, granulating and disintegratingagents, binding agents, lubricating agents, preservative agents andantioxidants. A further suitable pharmaceutically-acceptable excipientmay be a chelating agent. Tablet formulations may be uncoated or coatedeither to modify their disintegration and the subsequent absorption ofthe active ingredient within the gastrointestinal tract, or to improvetheir stability and/or appearance, in either case, using conventionalcoating agents and procedures well known in the art.

Compositions for oral use may alternatively be in the form of hardgelatin capsules in which the active ingredient is mixed with an inertsolid diluent, or as soft gelatin capsules in which the activeingredient is mixed with water or an oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, dispersing orwetting agents. The aqueous suspensions may also contain one or morepreservatives, anti-oxidants, colouring agents, flavouring agents,and/or sweetening agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil or in a mineral oil. The oily suspensions may alsocontain a thickening agent. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Additional excipients such as sweetening,flavouring and colouring agents, may also be present.

The pharmaceutical compositions of the present disclosure may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil or a mineral oil or a mixture of any of these. The emulsions mayalso contain sweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents, and mayalso contain a demulcent, preservative, flavouring and/or colouringagent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solventsystem.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient. Dry powder inhalers may also be suitable.

For further information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, oral administration to humans willgenerally require, for example, from 1 mg to 2 g of active agent (moresuitably from 100 mg to 2 g, for example from 250 mg to 1.8 g, such asfrom 500 mg to 1.8 g, particularly from 500 mg to 1.5 g, convenientlyfrom 500 mg to 1 g) to be administered compounded with an appropriateand convenient amount of excipients which may vary from about 3 to about98 percent by weight of the total composition. It will be understoodthat, if a large dosage is required, multiple dosage forms may berequired, for example two or more tablets or capsules, with the dose ofactive ingredient divided conveniently between them. Typically, unitdosage forms will contain about 10 mg to 0.5 g of a compound of thispresent disclosure, although a unit dosage form may contain up to 1 g.Conveniently, a single solid dosage form may contain between 1 and 300mg of active ingredient.

The size of the dose for therapeutic or prophylactic purposes ofcompounds of the present disclosure will naturally vary according to thenature and severity of the disease state, the age and sex of the animalor patient and the route of administration, according to well knownprinciples of medicine.

In using compounds of the present disclosure for therapeutic orprophylactic purposes it will generally be administered so that a dailydose in the range, for example, 1 mg/kg to 100 mg/kg body weight isreceived, given if required in divided doses. In general, lower doseswill be administered when a parenteral route is employed. Thus, forexample, for intravenous administration, a dose in the range, forexample, 1 mg/kg to 25 mg/kg body weight will generally be used.Similarly, for administration by inhalation, a dose in the range, forexample, 1 mg/kg to 25 mg/kg body weight will be used. Oraladministration is however preferred, particularly in tablet form.

In one aspect of the present disclosure, compounds of the presentdisclosure or pharmaceutically-acceptable salts thereof, areadministered as tablets comprising 10 mg to 500 mg of the compound ofFormula (I) (or a pharmaceutically-acceptable salt thereof), wherein oneor more tablets are administered as required to achieve the desireddose.

As stated above, it is known that signalling through ERK causestumourigenesis by one or more of the effects of mediating proliferationof cancer and other cells, mediating angiogenic events and mediating themotility, migration and invasiveness of cancer cells.

We have found that the compounds of the present disclosure possesspotent anti-tumour activity which it is believed is obtained by way ofinhibition of ERK that is involved in the signal transduction stepswhich lead to the proliferation and survival of tumour cells and theinvasiveness and migratory ability of metastasising tumour cells.

Accordingly, the compounds of the present disclosure may be of value asanti-tumour agents, in particular as selective inhibitors of theproliferation, survival, motility, dissemination and invasiveness ofmammalian cancer cells leading to inhibition of tumour growth andsurvival and to inhibition of metastatic tumour growth. Particularly,the compounds of the present disclosure may be of value asanti-proliferative and anti-invasive agents in the containment and/ortreatment of solid tumour disease. Particularly, the compounds of thepresent disclosure may be useful in the prevention or treatment of thosetumours which are sensitive to inhibition of ERK and that are involvedin the signal transduction steps which lead to the proliferation andsurvival of tumour cells and the migratory ability and invasiveness ofmetastasising tumour cells. Further, the compounds of the presentdisclosure may be useful in the prevention or treatment of those tumourswhich are mediated alone or in part by inhibition of ERK, i.e. thecompounds may be used to produce an ERK inhibitory effect in awarm-blooded animal in need of such treatment.

According to a further aspect there is provided a compound of theFormula (I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore for use as a medicament in a warm-blooded animal such asman.

According to a further aspect, there is provided a compound of theFormula (I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore for use in the production of an anti-proliferative effectin a warm-blooded animal such as man.

According to a further aspect there is provided a compound of theFormula (I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore for use in a warm-blooded animal such as man as ananti-invasive agent in the containment and/or treatment of solid tumourdisease.

According to a further aspect there is provided the use of a compound ofthe Formula (I), or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore, for the production of an anti-proliferative effectin a warm-blooded animal such as man.

According to a further aspect there is provided the use of a compound ofthe Formula (I), or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore, in the manufacture of a medicament for use in theproduction of an anti-proliferative effect in a warm-blooded animal suchas man.

According to a further aspect there is provided the use of a compound ofthe Formula (I), or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore, in the manufacture of a medicament for use in awarm-blooded animal such as man as an anti-invasive agent in thecontainment and/or treatment of solid tumour disease.

According to a further aspect there is provided a method for producingan anti-proliferative effect in a warm-blooded animal, such as man, inneed of such treatment which comprises administering to said animal aneffective amount of a compound of the Formula (I), or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect there is provided a method for producingan anti-invasive effect by the containment and/or treatment of solidtumour disease in a warm-blooded animal, such as man, in need of suchtreatment which comprises administering to said animal an effectiveamount of a compound of the Formula (I), or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect, there is provided a compound of theFormula (I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore, for use in the prevention or treatment of cancer in awarm-blooded animal such as man.

According to a further aspect there is provided the use of a compound ofthe Formula (I), or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore in the manufacture of a medicament for use in theprevention or treatment of cancer in a warm-blooded animal such as man.

According to a further aspect there is provided a method for theprevention or treatment of cancer in a warm-blooded animal, such as man,in need of such treatment which comprises administering to said animalan effective amount of a compound of the Formula (I), or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect, there is provided a compound of theFormula (I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore for use in the prevention or treatment of solid tumourdisease in a warm-blooded animal such as man.

According to a further aspect, there is provided the use of a compoundof the Formula (I), or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore, in the manufacture of a medicament for use in theprevention or treatment of solid tumour disease in a warm-blooded animalsuch as man.

According to a further aspect, there is provided a method for theprevention or treatment of solid tumour disease in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound of theFormula (I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore.

According to a further aspect, there is provided a method for reducingthe number of cancer cell in an individual in need of such treatmentwhich comprises administering to said animal an effective amount of acompound of the Formula (I), or a pharmaceutically-acceptable saltthereof, as defined hereinbefore.

According to a further aspect, there is provided a method for reducingthe size of a tumour in need of such treatment which comprisesadministering to said animal an effective amount of a compound of theFormula (I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore.

According to a further aspect, there is provided a method for reducingor inhibiting growth or proliferation of a tumour in need of suchtreatment which comprises administering to said animal an effectiveamount of a compound of the Formula (I), or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect, there is provided a method for preventingmetastasis or reducing the extent of metastasis in need of suchtreatment which comprises administering to said animal an effectiveamount of a compound of the Formula (I), or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect, there is provided a method for extendingthe survival (including but not limited to progression free survival(PFS) or overall survival) in an individual having or at risk of havingcancer in need of such treatment which comprises administering to saidanimal an effective amount of a compound of the Formula (I), or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

The phrase “effective amount” or “therapeutically-effective amount”means an amount that (i) treats the particular disease, condition ordisorder, (ii) attenuates, ameliorates or eliminates one or moresymptoms of the particular disease, condition or disorder, (iii) delaysor prevents the onset of one or more symptoms of the particular disease,condition or disorder described herein. In the case of cancer, theeffective amount may reduce the number of cancer cells; reduce thetumour size; inhibit (eg slow to some extent and preferably stop)infiltration of the cancer cells into peripheral organs; inhibit tumourmetastasis; inhibit to some extent tumour growth; and/or relieve to someextent one or more of the symptoms associated with cancer. For cancertherapy, efficacy can be measure by assessing, for example the time todisease progression (TTP) and/or assessing the response rate (RR).

According to a further aspect there is provided a compound of theFormula (I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore, for use in the prevention or treatment of ahyperproliferative disease or disorder modulated by RAS/RAF/MEK/ERKkinases.

According to a further aspect there is provided the use of a compound ofthe Formula (I), or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore, in the manufacture of a medicament for use in theprevention or treatment of a hyperproliferative disease or disordermodulated by RAS/RAF/MEK/ERK kinases.

According to a further aspect there is provided a method for theprevention or treatment of a hyperproliferative disease or disordermodulated by RAS/RAF/MEK/ERK kinases which comprises administering tosaid animal an effective amount of a compound of the Formula (I), or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect there is provided a compound of theFormula (I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore, for use in the prevention or treatment of ahyperproliferative disease or disorder mediated by ERK.

According to a further aspect there is provided the use of a compound ofthe Formula (I), or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore, in the manufacture of a medicament for use in theprevention or treatment of a hyperproliferative disease or disordermediated by ERK.

According to a further aspect there is provided a method for theprevention or treatment of a hyperproliferative disease or disordermediated by ERK which comprises administering to said animal aneffective amount of a compound of the Formula (I), or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect there is provided a compound of theFormula (I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore, for use in the prevention or treatment of those tumourswhich are sensitive to inhibition of ERK.

According to a further aspect there is provided the use of a compound ofthe Formula (I), or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore, in the manufacture of a medicament for use in theprevention or treatment of those tumours which are sensitive toinhibition of ERK.

According to a further aspect there is provided a method for theprevention or treatment of those tumours which are sensitive toinhibition of ERK which comprises administering to said animal aneffective amount of a compound of the Formula (I), or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect there is provided a compound of theFormula (I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore for use in providing an inhibitory effect on ERK.

According to a further aspect there is provided the use of a compound ofthe Formula (I), or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore in the manufacture of a medicament for use inproviding an inhibitory effect on ERK.

According to a further aspect there is also provided a method forproviding an inhibitory effect on ERK which comprises administering aneffective amount of a compound of the Formula (I), or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect there is provided a compound of theFormula (I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore, for use in providing a selective inhibitory effect onERK2.

According to a further aspect there is provided the use of a compound ofthe Formula (I), or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore, in the manufacture of a medicament for use inproviding a selective inhibitory effect on ERK2.

According to a further aspect there is also provided a method forproviding a selective inhibitory effect on ERK2 which comprisesadministering an effective amount of a compound of the Formula (I), or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

Compounds of Formula (I) may be effective in treating any cancer wherethe RAS/RAF/MEK/ERK kinase pathway is activated. Examples of cancerswhich have been reported to have such activation include acutemyelogenous leukemia (AML), chronic myelomonocyic leukemia, multiplemyeloma, chronic myelogenous leukemia, colorectal cancer (CRC), breastcancer, bladder cancer, head and neck cancer, brain cancer,glioblastoma, neuroblastoma, Non-Hodgkins lymphoma, pancreatic cancer,ovarian cancer, testicular cancer, thyroid cancer, non-small cell lungcancer (NSCLC), small cell lung cancer, melanoma, neurofibromatosis type1 (NF1), biliary tract.

In one aspect, compounds may be effective in treating a cancer selectedfrom NSCLC, pancreatic, CRC, melanoma, uveal melanoma, paediatric NF1,differentiated thyroid and biliary tract cancer.

In one aspect, compounds may be effective in treating KRAS or BRAFmutant cancers.

In one aspect, compounds may be effective in treating MAPK pathwaydependent cancers such as NSCLC, pancreatic and CRC; in some embodimentssuch cancers are KRAS mutant cancers as described hereinafter.

In another aspect, compounds may be effective in treating BRAF mutantmelanoma.

In a further aspect, compounds may be effective in treating a cancerselected from NRAS mutant melanoma, uveal melanoma, paediatric NF1,differentiated thyroid and biliary tract cancer.

According to a further aspect there is provided a compound of theFormula (I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore, for use in the treatment of NSCLC, pancreatic, CRC,melanoma, uveal melanoma, paediatric NF1, differentiated thyroid andbiliary tract cancers.

According to a further aspect there is provided a compound of theFormula (I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore, for use in the treatment of NSCLC, pancreatic and CRC.

According to a further aspect there is provided a compound of theFormula (I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore, for use in the treatment of BRAF mutant melanoma.

According to a further aspect there is provided a compound of theFormula (I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore, for use in the treatment of NRAS mutant melanoma, uvealmelanoma, paediatric NF1, differentiated thyroid and biliary tractcancer.

According to a further aspect there is provided a compound of theFormula (I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore, for use in the treatment of a cancer mediated by ERK,wherein the cancer has developed resistance to one or more other MAPKpathway inhibitors.

According to a further aspect there is provided a method for treating acancer selected from NSCLC, pancreatic, CRC, melanoma, uveal melanoma,paediatric NF1, differentiated thyroid and biliary tract cancers, whichcomprises administering an effective amount of a compound of the Formula(I), or a pharmaceutically-acceptable salt thereof, as definedhereinbefore.

According to a further aspect there is provided a method for treating acancer selected from NSCLC, pancreatic and CRC, which comprisesadministering an effective amount of a compound of the Formula (I), or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect there is provided a method for treatingBRAF mutant melanoma, which comprises administering an effective amountof a compound of the Formula (I), or a pharmaceutically-acceptable saltthereof, as defined hereinbefore.

According to a further aspect there is provided a method for treating acancer selected from NRAS mutant melanoma, uveal melanoma, paediatricNF1, differentiated thyroid and biliary tract cancer, which comprisesadministering an effective amount of a compound of the Formula (I), or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect there is provided a method for treating acancer mediated by ERK, wherein the cancer has developed resistance toone or more other MAPK pathway inhibitors, which comprises administeringan effective amount of a compound of the Formula (I), or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect there is provided the use of a compound ofthe Formula (I), or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore, in the manufacture of a medicament for use in thetreatment of a cancer selected from NSCLC, pancreatic, CRC, melanoma,uveal melanoma, paediatric NF1, differentiated thyroid and biliary tractcancers.

According to a further aspect there is provided the use of a compound ofthe Formula (I), or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore, in the manufacture of a medicament for use in thetreatment of a cancer selected from NSCLC, pancreatic and CRC.

According to a further aspect there is provided the use of a compound ofthe Formula (I), or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore, in the manufacture of a medicament for use in thetreatment of BRAF mutant melanoma.

According to a further aspect there is provided the use of a compound ofthe Formula (I), or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore, in the manufacture of a medicament for use in thetreatment of NRAS mutant melanoma, uveal melanoma, paediatric NF1,differentiated thyroid and biliary tract cancer.

According to a further aspect there is provided the use of a compound ofthe Formula (I), or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore, in the manufacture of a medicament for use in thetreatment of a cancer mediated by ERK, wherein the cancer has developedresistance to one or more other MAPK pathway inhibitors.

As stated hereinbefore, the in-vivo effects of a compound of the Formula(I) may be exerted in part by one or more metabolites that are formedwithin the human or animal body after administration of a compound ofthe Formula (I).

In the above compositions, methods and uses, particular compounds ofFormula (I) are the compounds of the Examples, orpharmaceutically-acceptable salts thereof. Further illustrative examplesfor compositions, methods and uses are:

-   2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-methylpyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3-chlorobenzyl)-6-methyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3-chloro-4-fluorobenzyl)-6-methyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3,4-difluorobenzyl)-6-methyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   2-(5-Methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-(3-methoxybenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6-methyl-7-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6-methyl-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6-methyl-7-((6-methylpyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   7-(3-chloro-4-fluorobenzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   7-(3-chlorobenzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   7-(3-(difluoromethyl)benzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   7-((6-(difluoromethyl)pyridin-2-yl)methyl)-2-(5-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-(3-chlorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3-chlorobenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3,4-difluorobenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3-(difluoromethyl)benzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3,5-difluorobenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3-methoxybenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(4-fluoro-3-methoxybenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3-(difluoromethoxy)benzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((4-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((2-(trifluoromethyl)pyridin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-((4-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   7-(3,4-Difluorobenzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one    Ethanesulfonic acid adduct;-   (R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one    Adipic acid adduct;-   (R)-6-Methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-((6-(Difluoromethyl)pyridin-2-yl)methyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   is    (R)-7-(3-(difluoromethyl)benzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-6-(Methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-(3,5-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;    and-   (R)-7-(3-Methoxybenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one.

The anti-cancer treatment defined herein may be applied as a soletherapy or may involve, in addition to the compounds of the presentdisclosure, conventional surgery or radiotherapy or chemotherapy. Incertain embodiments, a compound of formula (I) is combined with anothercompound which has anti-hyperproliferative properties or that is usefulin treating a hyperproliferative disorder. The additional compound maysuitably have complementary activities to the compound of formula (I)such that they do not adversely affect each other. In some aspects suchcombination therapy may prevent or delay inherent or acquired resistanceattributable to activation of the RAS/RAF/MEK/ERK pathway observed withMEK inhibition and to prevent or delay inherent or acquired resistancemediated via RAS pathway activation.

In addition to providing improved treatment for a givenhyperproliferative disorder, administration of certain combinations mayimprove the quality of life of a patient compared to the quality of lifeexperienced by the same patient receiving a different treatment. Forexample, administration of a combination to a patient may provide animproved quality of life compared to the quality of life the samepatient would experience if they received only one of the individualagents as therapy. For example, a combined therapy may lower the dose ofthe therapeutic agents required. The combination may also cause reducedtumour burden and thereby reduce the associated adverse events.

Accordingly, in one embodiment there is provided a compound of Formula(I), or a pharmaceutically-acceptable salt thereof, and an additionalanti-tumour substance for the conjoint treatment of cancer.

The anti-cancer treatment defined hereinbefore may be applied as a soletherapy or may involve, in addition to the compound of the presentdisclosure, conventional surgery or radiotherapy or chemotherapy. Suchchemotherapy may include one or more of the following categories ofanti-tumour agents:—

(i) antiproliferative/antineoplastic drugs and combinations thereof, asused in medical oncology, such as alkylating agents (for examplecis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chlorambucil, busulphan, temozolamide andnitrosoureas); antimetabolites (for example gemcitabine and antifolatessuch as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,methotrexate, cytosine arabinoside, and hydroxyurea); antitumourantibiotics (for example anthracyclines like adriamycin, bleomycin,doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and taxotere and polokinase inhibitors); andtopoisomerase inhibitors (for example epipodophyllotoxins like etoposideand teniposide, amsacrine, topotecan and camptothecin);(ii) antihormonal agents such as antioestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of 5α-reductase suchas finasteride;(iii) inhibitors of growth factor function and their downstreamsignalling pathways: included are Ab modulators of any growth factor orgrowth factor receptor targets, reviewed by Stern et al. CriticalReviews in Oncology/Haematology, 2005, 54, pp 11-29); also included aresmall molecule inhibitors of such targets, for example kinaseinhibitors—examples include the anti-erbB2 antibody trastuzumab[Herceptin™], the anti-EGFR antibody panitumumab, the anti-EGFR antibodycetuximab [Erbitux, C225] and tyrosine kinase inhibitors includinginhibitors of the erbB receptor family, such as epidermal growth factorfamily receptor (EGFR/erbB1) tyrosine kinase inhibitors such asgefitinib or erlotinib, erbB2 tyrosine kinase inhibitors such aslapatinib, and mixed erb1/2 inhibitors such as afatanib; similarstrategies are available for other classes of growth factors and theirreceptors, for example inhibitors of the hepatocyte growth factor familyor their receptors including c-met and ron; inhibitors of the insulinand insulin growth factor family or their receptors (IGFR, IR)inhibitors of the platelet-derived growth factor family or theirreceptors (PDGFR), and inhibitors of signalling mediated by otherreceptor tyrosine kinases such as c-kit, AnLK, and CSF-1R;also included are modulators which target signalling proteins in thewider PI3-kinase signalling pathway, for example, inhibitors of otherPI3-kinase isoforms such as PI3K-β, and ser/thr kinases such as AKT,mTOR, PDK, SGK, PI4K or PIP5K;also included are inhibitors of serine/threonine kinases not listedabove, for example raf inhibitors such as vemurafenib, MEK inhibitorssuch as selumetinib (AZD6244, ARRY-142886), cobimetinib or GDC-0623 (seefor example WO2015/0832840), Abl inhibitors such as imatinib ornilotinib, Btk inhibitors such as ibrutinib, Syk inhibitors such asfostamatinib, aurora kinase inhibitors (for example AZD1152), inhibitorsof other ser/thr kinases such as JAKs, STATs and IRAK4, and cyclindependent kinase inhibitors;iv) modulators of DNA damage signalling pathways, for example PARPinhibitors (e.g. Olaparib), ATR inhibitors or ATM inhibitors;v) modulators of apoptotic and cell death pathways such as Bcl familymodulators (e.g. ABT-263/Navitoclax, ABT-199);(vi) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™) and forexample, a VEGF receptor tyrosine kinase inhibitor such as sorafenib,axitinib, pazopanib, sunitinib and vandetanib (and compounds that workby other mechanisms (for example linomide, inhibitors of integrin avβ3function and angiostatin)];(vii) vascular damaging agents, such as Combretastatin A4;(viii) anti-invasion agents, for example c-Src kinase family inhibitorslike (dasatinib, J. Med. Chem., 2004, 47, 6658-6661) and bosutinib(SKI-606), and metalloproteinase inhibitors like marimastat, inhibitorsof urokinase plasminogen activator receptor function or antibodies toHeparanase];(ix) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies. Specific examples include monoclonalantibodies targeting PD-1 (e.g. BMS-936558), PDL-1 or CTLA4 (e.g.ipilimumab and tremelimumab);(x) Antisense or RNAi based therapies, for example those which aredirected to the targets listed.(xi) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy.

According to this aspect there is provided a combination suitable foruse in the treatment of cancer comprising a compound of Formula (I) asdefined hereinbefore or a pharmaceutically-acceptable salt thereof andanother anti-tumour agent, in particular any one of the anti tumouragents listed under (i)-(xi) above. In particular, the anti-tumour agentlisted under (i)-(xi) above is the standard of care for the specificcancer to be treated; the person skilled in the art will understand themeaning of “standard of care”.

Therefore in a further aspect there is provided a compound of Formula(I) or a pharmaceutically-acceptable salt thereof in combination withanother anti-tumour agent, in particular an anti-tumour agent selectedfrom one listed under (i)-(xi) herein above.

According to a further aspect there is provided a pharmaceuticalcomposition which comprises a compound of Formula (I) or apharmaceutically-acceptable salt thereof in combination with ananti-tumour agent selected from one listed under (i)-(xi) herein above,in association with a pharmaceutically-acceptable diluent or carrier.

According to a further aspect there is provided a pharmaceuticalcomposition which comprises a compound of Formula (I) or apharmaceutically-acceptable salt thereof in combination with ananti-tumour agent selected from one listed under (i)-(xi) herein above,in association with a pharmaceutically-acceptable diluent or carrier foruse in treating cancer.

According to another feature there is provided the use of a compound ofthe Formula (I) or a pharmaceutically-acceptable salt thereof incombination with an anti-tumour agent selected from one listed under(i)-(xi) herein above, in the manufacture of a medicament for use incancer in a warm-blooded animal, such as man.

According to another feature, there is provided a method of treatingcancer in a warm-blooded animal, such as man, in need of such treatmentwhich comprises administering to said animal an effective amount of acompound of Formula (I) or a pharmaceutically-acceptable salt thereof incombination with an anti-tumour agent selected from one listed under(i)-(xi) herein above.

In a further aspect there is provided a compound of Formula (I) or apharmaceutically-acceptable salt thereof in combination with anotheranti-tumour agent, in particular an anti-tumour agent selected from onelisted under (i) above.

In a further aspect there is provided a combination suitable for use inthe treatment of cancer comprising a compound of Formula (I) as definedhereinbefore or a pharmaceutically-acceptable salt thereof and any oneof the anti tumour agents listed under (i) above.

According to a further aspect there is provided a pharmaceuticalcomposition which comprises a compound of Formula (I) or apharmaceutically-acceptable salt thereof in combination with ananti-tumour agent selected from one listed under (i) herein above, inassociation with a pharmaceutically-acceptable diluent or carrier.

According to a further aspect there is provided a pharmaceuticalcomposition which comprises a compound of Formula (I) or apharmaceutically-acceptable salt thereof in combination with ananti-tumour agent selected from one listed under (i) herein above, inassociation with a pharmaceutically-acceptable diluent or carrier foruse in treating cancer.

According to another feature there is provided the use of a compound ofthe Formula (I) or a pharmaceutically-acceptable salt thereof incombination with an anti-tumour agent selected from one listed under (i)herein above, in the manufacture of a medicament for use in cancer in awarm-blooded animal, such as man.

According to another feature, there is provided a method of treatingcancer in a warm-blooded animal, such as man, in need of such treatmentwhich comprises administering to said animal an effective amount of acompound of Formula (I) or a pharmaceutically-acceptable salt thereof incombination with an anti-tumour agent selected from one listed under (i)herein above.

In a further aspect there is provided a compound of Formula (I) or apharmaceutically-acceptable salt thereof in combination with anotheranti-tumour agent, in particular an anti-tumour agent selected from onelisted under (iii) above.

In a further aspect there is provided a combination suitable for use inthe treatment of cancer comprising a compound of Formula (I) as definedhereinbefore or a pharmaceutically-acceptable salt thereof and any oneof the anti tumour agents listed under (iii) above.

According to a further aspect there is provided a pharmaceuticalcomposition which comprises a compound of Formula (I) or apharmaceutically-acceptable salt thereof in combination with ananti-tumour agent selected from one listed under (iii) herein above, inassociation with a pharmaceutically-acceptable diluent or carrier.

According to a further aspect there is provided a pharmaceuticalcomposition which comprises a compound of Formula (I) or apharmaceutically-acceptable salt thereof in combination with ananti-tumour agent selected from one listed under (iii) herein above, inassociation with a pharmaceutically-acceptable diluent or carrier foruse in treating cancer.

According to another feature there is provided the use of a compound ofthe Formula (I) or a pharmaceutically-acceptable salt thereof incombination with an anti-tumour agent selected from one listed under(iii) herein above, in the manufacture of a medicament for use in cancerin a warm-blooded animal, such as man.

According to another feature, there is provided a method of treatingcancer in a warm-blooded animal, such as man, in need of such treatmentwhich comprises administering to said animal an effective amount of acompound of Formula (I) or a pharmaceutically-acceptable salt thereof incombination with an anti-tumour agent selected from one listed under(iii) herein above.

In one aspect, suitable examples of anti tumour agents listed in (iii)above are those agents which also act on MAPK kinsases, particularly onthe RAS-RAF-MEK-ERK signalling cascade such as MEK inhibitors.

In a further aspect there is provided a combination suitable for use inthe treatment of cancer comprising a compound of Formula (I) as definedhereinbefore or a pharmaceutically-acceptable salt thereof and a MEKinhibitor, such as selumetinib (ARRY-142886).

In one aspect, the above combination of the compound of formula (I) andselumetinib (ARRY-142886) is suitable for use in the treatment of anycancer dependent on the MAPK pathway, such as NSCLC, pancreatic or CRcancer, optionally in combination with standard of care therapy.

The combination of a compound of Formula (I) and an anti-tumour agentlisted in (iii) above, particularly another agent acting on MAPKkinases, particularly on the RAS-RAF-MEK-ERK signalling cascade such asMEK inhibitors/may be particularly useful in treating tumours with ahigher prevalence of mutation in KRAS or BRAF.

Particular combinations of the present disclosure comprise any one ofthe compounds of the Examples herein (or a pharmaceutically-acceptablesalt thereof) and a MEK inhibitor such as selumetinib (ARRY-142886) asdescribed hereinabove. Further illustrative examples for combinations ofthe present disclosure and a MEK inhibitor such as selumetinib(ARRY-14288) are:

-   2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-methylpyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3-chlorobenzyl)-6-methyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3-chloro-4-fluorobenzyl)-6-methyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3,4-difluorobenzyl)-6-methyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   2-(5-Methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-(3-methoxybenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6-methyl-7-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6-methyl-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6-methyl-7-((6-methylpyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   7-(3-chloro-4-fluorobenzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   7-(3-chlorobenzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   7-(3-(difluoromethyl)benzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   7-((6-(difluoromethyl)pyridin-2-yl)methyl)-2-(5-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-(3-chlorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3-chlorobenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3,4-difluorobenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3-(difluoromethyl)benzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3,5-difluorobenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3-methoxybenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(4-fluoro-3-methoxybenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3-(difluoromethoxy)benzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((4-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((2-(trifluoromethyl)pyridin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-((4-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   7-(3,4-Difluorobenzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (S)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one    Ethanesulfonic acid adduct;-   (R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one    Adipic acid adduct;-   (R)-6-Methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-((6-(Difluoromethyl)pyridin-2-yl)methyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-7-(3-(difluoromethyl)benzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   (R)-6-(Methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;-   is    (R)-7-(3,5-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;    and-   (R)-7-(3-Methoxybenzyl)-6-(methoxymethyl)-2-(5-methyl-2e    1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one.

In all of the above combinations, it will be understood that thecombination may also be dosed with standard of care treatment, asunderstood by the skilled person, such as other treatments from (i) to(xi) hereinbefore. In other aspects, suitably the standard of care maybe selected from (i) above.

Therefore in a further aspect of the present disclosure, there isprovided a triple combination suitable for use in the treatment ofcancer

-   -   a) a compound of formula (I) or a pharmaceutically-acceptable        salt thereof;    -   b) a compound selected from (iii) above (such as another        compound acting on MAPK kinases) or a        pharmaceutically-acceptable salt thereof; and    -   c) standard of care therapy for the cancer to be treated.

Suitably standard of care therapy may be dosed according to its usualdosing regimen, as understood by the skilled person.

According to a further aspect there is provided a kit comprising acompound of Formula (I) or a pharmaceutically-acceptable salt thereof incombination with an anti-tumour agent selected from one listed under(i)-(xi) herein above.

According to a further aspect there is provided a kit comprising:

a) a compound of Formula (I) or a pharmaceutically-acceptable saltthereof in a first unit dosage form;b) an anti-tumour agent selected from one listed under (i)-(xi) hereinabove in a second unit dosage form; andc) container means for containing said first and second dosage forms.

According to a further aspect there is provided a kit comprising:

a) a compound of Formula (I) or a pharmaceutically-acceptable saltthereof in a first unit dosage form;b) an anti-tumour agent selected from one listed under (i)-(xi) hereinabove in a second unit dosage form;c) container means for containing said first and second dosage forms;and optionallyd) instructions for use.

Herein, where the term “combination” is used it is to be understood thatthis refers simultaneous, separate or sequential administration. In oneaspect of the present disclosure “combination” refers to simultaneousadministration. In another aspect of the present disclosure“combination” refers to separate administration. In a further aspect ofthe present disclosure “combination” refers to sequentialadministration. Where the administration is sequential or separate, thedelay in administering the second component should not be such as tolose the beneficial effect.

Although the compounds of the Formula (I) are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit ERK. Thus, they areuseful as pharmacological standards for use in the development of newbiological tests and in the search for new pharmacological agents.

Personalised Healthcare

Another aspect of the present disclosure is based on identifying a linkbetween the status of the gene encoding KRAS and susceptibility totreatment with a compound of Formula (I). This therefore providesopportunities, methods and tools for selecting patients for treatmentwith a compound of Formula (I), particularly cancer patients, and/oravoiding treatment of patients less likely to respond therapeutically tothe treatment thus avoiding unnecessary treatment and any side effectsthat may be associated with such ineffective treatment.

The present disclosure relates to patient selection tools and methods(including personalised medicine). The selection is based on whether thetumour cells to be treated possess wild-type or mutant KRAS gene. TheKRAS gene status can therefore be used as a biomarker of susceptibilityto treatment with an ERK inhibitor.

There is a clear need for biomarkers that will enrich for or selectpatients whose tumours will respond to treatment with an ERK inhibitor,such as a compound of Formula (I). Patient selection biomarkers thatidentify the patients most likely to respond to an agent are ideal inthe treatment of cancer, since they reduce the unnecessary treatment ofpatients with non-responding tumours to the potential side effects ofsuch agents.

A biomarker can be described as “a characteristic that is objectivelymeasured and evaluated as an indicator of normal biologic processes,pathogenic processes, or pharmacologic responses to a therapeuticintervention”. A biomarker is any identifiable and measurable indicatorassociated with a particular condition or disease where there is acorrelation between the presence or level of the biomarker and someaspect of the condition or disease (including the presence of, the levelor changing level of, the type of, the stage of, the susceptibility tothe condition or disease, or the responsiveness to a drug used fortreating the condition or disease). The correlation may be qualitative,quantitative, or both qualitative and quantitative. Typically abiomarker is a compound, compound fragment or group of compounds. Suchcompounds may be any compounds found in or produced by an organism,including proteins (and peptides), nucleic acids and other compounds.

Biomarkers may have a predictive power, and as such may be used topredict or detect the presence, level, type or stage of particularconditions or diseases (including the presence or level of particularmicroorganisms or toxins), the susceptibility (including geneticsusceptibility) to particular conditions or diseases, or the response toparticular treatments (including drug treatments). It is thought thatbiomarkers will play an increasingly important role in the future ofdrug discovery and development, by improving the efficiency of researchand development programs. Biomarkers can be used as diagnostic agents,monitors of disease progression, monitors of treatment and predictors ofclinical outcome. For example, various biomarker research projects areattempting to identify markers of specific cancers and of specificcardiovascular and immunological diseases. It is believed that thedevelopment of new validated biomarkers will lead both to significantreductions in healthcare and drug development costs and to significantimprovements in treatment for a wide variety of diseases and conditions.

In order to optimally design clinical trials and to gain the mostinformation from these trials, a biomarker may be required. The markermay be measurable in surrogate and tumour tissues. Ideally these markerswill also correlate with efficacy and thus could ultimately be used forpatient selection.

Thus, the technical problem underlying this aspect of the presentdisclosure is the identification of means for stratification of patientsfor treatment with a compound of Formula (I). The technical problem issolved by provision of the embodiments characterized in the claimsand/or description herein.

The present disclosure provides a method of determining sensitivity ofcells to a compound of Formula (I). The method comprises determining thestatus of KRAS gene in said cells. The cells are identified as likely tobe sensitive to a compound of Formula I if the cells possess a mutatedKRAS gene. Those patients with a mutated KRAS gene are thereforepredicted to be particularly susceptible to treatment with a compound ofFormula (I). A cell is defined as sensitive to a compound of Formula (I)if it inhibits the increase in cell number in a cell growth assay(either through inhibition of cell proliferation and/or throughincreased cell death). Methods of the present disclosure are useful forpredicting which cells are more likely to respond to a compound ofFormula (I) by growth inhibition.

The present disclosure is further based, in part, on methods that can beused to determine a patient's responsiveness to a compound of Formula(I) including determining whether to administer a compound of Formula(I). Specifically the methods of the present disclosure include thedetermination of the gene status of KRAS. The presence of a mutated KRASgene indicates that the tumour cells are more likely to respond bygrowth inhibition when contacted with a compound of Formula (I). TheKRAS gene status can therefore be used to select patients for treatmentwith a compound of Formula (I).

A sample “representative of the tumour” can be the actual tumour sampleisolated, or may be a sample that has been further processed, e.g. asample of PCR amplified nucleic acid from the tumour sample.

Definitions

In this Personalised Healthcare section:

“Allele” refers to a particular form of a genetic locus, distinguishedfrom other forms by its particular nucleotide or amino acid sequence.

“Amplification reactions” are nucleic acid reactions which result inspecific amplification of target nucleic acids over non-target nucleicacids. The polymerase chain reaction (PCR) is a well known amplificationreaction.

“Cancer” is used herein to refer to neoplastic growth arising fromcellular transformation to a neoplastic phenotype. Such cellulartransformation often involves genetic mutation.

“Gene” is a segment of DNA that contains all the information for theregulated biosynthesis of an RNA product, including a promoter, exons,introns, and other sequence elements which may be located within 5′ or3′ flanking regions (not within the transcribed portions of the gene)that control expression.

“Gene status” refers to whether the gene is wild type or not (i.e.mutant).

“Label” refers to a composition capable of producing a detectable signalindicative of the presence of the target polynucleotide in an assaysample. Suitable labels include radioisotopes, nucleotide chromophores,enzymes, substrates, fluorescent molecules, chemiluminescent moieties,magnetic particles, bioluminescent moieties, and the like. As such, alabel is any composition detectable by spectroscopic, photochemical,biochemical, immunochemical, electrical, optical or chemical means.

“Non-synonymous variation” refers to a variation (variance) in oroverlapping the coding sequence of a gene that result in the productionof a distinct (altered) polypeptide sequence. These variations may ormay not affect protein function and include missense variants (resultingin substitution of one amino acid for another), nonsense variants(resulting in a truncated polypeptide due to generation of a prematurestop codon) and insertion/deletion variants.

“Synonymous variation” refers to a variation (variance) in the codingsequence of a gene that does not affect sequence of the encodedpolypeptide. These variations may affect protein function indirectly(for example by altering expression of the gene), but, in the absence ofevidence to the contrary, are generally assumed to be innocuous.

“Nucleic acid” refers to single stranded or double stranded DNA and RNAmolecules including natural nucleic acids found in nature and/ormodified, artificial nucleic acids having modified backbones or bases,as are known in the art.

“Primer” refers to a single stranded DNA oligonucleotide sequencecapable of acting as a point of initiation for synthesis of a primerextension product which is complementary to the nucleic acid strand tobe copied. The length and sequence of the primer must be such that theyare able to prime the synthesis of extension products. A typical primercontains at least about 7 nucleotides in length of a sequencesubstantially complementary to the target sequence, but somewhat longerprimers are preferred. Usually primers contain about 15-26 nucleotides,but longer or shorter primers may also be employed.

“Polymorphic site” is a position within a locus at which at least twoalternative sequences are found in a population.

“Polymorphism” refers to the sequence variation observed in anindividual at a polymorphic site. Polymorphisms include nucleotidesubstitutions, insertions, deletions and microsatellites and may, butneed not, result in detectable differences in gene expression or proteinfunction. In the absence of evidence of an effect on expression orprotein function, common polymorphisms, including non-synonomousvariants, are generally considered to be included in the definition ofwild-type gene sequence. A catalog of human polymorphisms and associatedannotation, including validation, observed frequencies, and diseaseassociation, is maintained by NCBI (dbSNP:http://www.ncbi.nlm.nih.gov/projects/SNP/). Please note that the term“polymorphism” when used in the context of gene sequences should not beconfused with the term “polymorphism” when used in the context of solidstate form of a compound, that is the crystalline or amorphous nature ofa compound. The skilled person will understand the intended meaning byits context.

“Probe” refers to single stranded sequence-specific oligonucleotideswhich have a sequence that is exactly complementary to the targetsequence of the allele to be detected.

“Response” is defined by measurements taken according to ResponseEvaluation Criteria in Solid Tumours (RECIST) involving theclassification of patients into two main groups: those that show apartial response or stable disease and those that show signs ofprogressive disease.

“Stringent hybridisation conditions” refers to an overnight incubationat 42° C. in a solution comprising 50% formamide, 5×SSC (750 mM NaCl, 75mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5×Denhardt'ssolution, 10% dextran sulphate, and 20 pg/mI denatured, sheared salmonsperm DNA, followed by washing the filters in 0.1×SSC at about 65° C.

“Survival” encompasses a patients' overall survival and progression-freesurvival.

“Overall survival” (OS) is defined as the time from the initiation ofdrug administration to death from any cause. “Progression-free survival”(PFS) is defined as the time from the initiation of drug administrationto first appearance of progressive disease or death from any cause.

According to one aspect, the present disclosure provides a method forselecting a cancer patient suitable for treatment with a compound ofFormula (I), the method comprising;

(a) testing a cancer patient to determine whether the KRAS gene in thepatient's tumour is wild type or mutant; and selecting a patient fortreatment with a compound of Formula (I) based thereon.

In one embodiment, the status of the KRAS gene in a patient's tumour isdetermining from a biological sample obtained from said patient In oneembodiment the biological sample is a tumour cell containing sample. Inone embodiment the biological sample is one that contains tumour DNA,such as a blood sample. According to one aspect of the presentdisclosure there is provided a method for selecting a patient fortreatment with a compound of Formula (I), the method comprisingobtaining a sample from a patient that comprises tumour cells or nucleicacid from the tumour cell; determining whether the KRAS gene in thepatient's tumour cells is wild type or mutant; and selecting a patientfor treatment with a compound of Formula (I) based thereon.

The method may include or exclude the actual patient sample isolationstep. Thus, according to one aspect of the present disclosure there isprovided a method for selecting a patient for treatment with a compoundof Formula (I), the method comprising determining whether the KRAS genein a tumour cell or nucleic acid containing sample previously isolatedfrom the patient is wild type or mutant; and selecting a patient fortreatment with a compound of Formula (I) based thereon.

In one embodiment, the patient is selected for treatment with a compoundof Formula (I) if the tumour cell has a mutant KRAS gene.

According to another aspect of the present disclosure there is provideda method for predicting a patient's responsiveness to a compound ofFormula (I), the method comprising determining whether the KRAS gene inthe patient's tumour cells is wild type or mutant and based thereon,predicting a patient's responsiveness to treatment with a compound ofFormula (I).

According to another aspect of the present disclosure there is provideda method for determining the likelihood of effectiveness of treatmentwith a compound of formula I in a human patient affected with cancercomprising: determining whether the KRAS gene(s) in the patient's tumourcells is wild type or mutant and based thereon, predicting a patient'sresponsiveness to treatment with a compound of Formula (I). For thepurpose of the present disclosure, a gene status of wild-type is meantto indicate normal or appropriate expression of the gene and normalfunction of the encoded protein. In contrast, mutant status is meant toindicate abnormal or inappropriate gene expression, or expression of aprotein with altered function, consistent with the known roles of mutantKRAS in cancer (as described herein). Any number of genetic orepigenetic alterations, including but not limited to mutation,amplification, deletion, genomic rearrangement, or changes inmethylation profile, may result in a mutant status. However, if suchalterations nevertheless result in appropriate expression of the normalprotein, or a functionally equivalent variant, then the gene status isregarded as wild-type. Examples of variants that typically would notresult in a functional mutant gene status include synonomous codingvariants and common polymorphisms (synonymous or non-synonymous). Asdiscussed below, gene status can be assessed by a functional assay, orit may be inferred from the nature of detected deviations from areference sequence.

In certain embodiments the wild-type or mutant status of the KRAS geneis determined by the presence or absence of non-synonymous nucleic acidvariations in the genes. Observed non-synonymous variationscorresponding to known common polymorphisms with no annotated functionaleffects do not contribute to a gene status of mutant.

KRAS Gene Bank Accession Details: KRAS NM_004985

It will be apparent that the gene and mRNA sequences disclosed for KRASand the KRAS protein sequence are each a representative sequence. Innormal individuals there are two copies of each gene, a maternal andpaternal copy, which will likely have some sequence differences,moreover within a population there will exist numerous allelic variantsof the gene sequence. Other sequences regarded as wild type includethose that possess one or more synonymous changes to the nucleic acidsequence (which changes do not alter the encoded protein sequence),non-synonymous common polymorphisms (e.g. germ-line polymorphisms) whichalter the protein sequence but do not affect protein function, andintronic non-splice-site sequence changes.

According to another aspect of the present disclosure there is provideda method for determining the likelihood of effectiveness of treatmentwith a compound of Formula (I) in a human patient affected with cancercomprising: detecting the presence or absence of at least onenon-synonymous nucleic acid variance in the KRAS gene of said patientrelative to the wild type gene, wherein the presence of at least onesomatic non-synonymous nucleic acid variance in the KRAS gene indicatesthat treatment with the compound of Formula (I) is likely to beeffective.

According to another aspect of the present disclosure there is provideda method for assessing the susceptibility of an individual to treatmentwith a compound of Formula (I), which method comprises:

-   -   (i) determining the non-synonymous mutation status of the KRAS        gene in tumour cell nucleic acid from the individual; and,    -   (ii) determining the likely susceptibility of the individual to        treatment with a compound of Formula (I) by reference to the        non-synonymous mutation status of the KRAS gene in the tumour        cells.

There are numerous techniques available to the person skilled in the artto determine the gene status of KRAS. The gene status can be determinedby determination of the nucleic acid sequence. This could be via directsequencing of the full-length gene or analysis of specific sites withinthe gene, e.g. commonly mutated sites.

An alternative means for determining whether or not the KRAS gene iswild type or mutant is to assess the function of the transcribed gene.Functional mutation of this KRAS gene produces a protein that hasimpaired GTP hydrolysis capability. Mutant KRAS persists in an active,GTP-bound state, leading to constitutive and deregulated stimulation ofdownstream signalling of the pathway in cells, including but not limitedto activation of Raf, PI3K and Ral pathways.

The assays to assess the functional status of KRAS variants whenexpressed in cells include but are not limited to:

(i) increased binding to the Ras binding domain (RBD) of Raf1(ii) increased levels of phosphorylated ERK1/2, MEK1/2, or Akt;(iii) increased focus and colony formation of NIH-3T3 cells transfectedwith the variant of KRAS

Samples

The patient's sample to be tested for the gene status can be any tumourtissue, tumour-cell containing or tumour nucleic acid containing sampleobtained or obtainable from the individual. The test sample isconveniently a sample of blood, mouth swab, biopsy, or other body fluidor tissue obtained from an individual. Particular examples include:circulating tumour cells, circulating DNA in the plasma or serum, cellsisolated from the ascites fluid of ovarian cancer patients, lung sputumfor patients with tumours within the lung, a fine needle aspirate from abreast cancer patient, urine, peripheral blood, a cell scraping, a hairfollicle, a skin punch or a buccal sample.

It will be appreciated that the test sample may equally be a nucleicacid sequence corresponding to the sequence in the test sample, that isto say that all or a part of the region in the sample nucleic acid mayfirstly be amplified using any convenient technique e.g. polymerasechain reaction (PCR), before analysis. The nucleic acid may be genomicDNA or fractionated or whole cell RNA. In particular embodiments the RNAis whole cell RNA and is used directly as the template for labelling afirst strand cDNA using random primers or poly A primers. The nucleicacid or protein in the test sample may be extracted from the sampleaccording to standard methodologies (see Green & Sambrook, Eds.,Molecular Cloning: A Laboratory Manual, (2012, 4th edition, Vol. 1-3,ISBN 9781936113422), Cold Spring Harbor Laboratory Press, Cold SpringHarbor, N.Y.).

The diagnostic methods of the present disclosure can be undertaken usinga sample previously taken from the individual or patient. Such samplesmay be preserved by freezing or fixed and embedded in formalin-paraffinor other media. Alternatively, a fresh tumour cell containing sample maybe obtained and used.

The methods of the present disclosure can be applied using cells fromany tumour. Suitable tumours for treatment with a compound of Formula(I) have been described hereinbefore.

Methods for Detection of Nucleic Acids

The detection of mutant KRAS nucleic acids can be employed, in thecontext of the present disclosure, to predict the response to drugtreatment. Since mutations in these genes occur at the DNA level, themethods of the present disclosure can be based on detection of mutationsor variances in genomic DNA, as well as transcripts and proteinsthemselves. It can be desirable to confirm mutations in genomic DNA byanalysis of transcripts and/or polypeptides, in order to ensure that thedetected mutation is indeed expressed in the subject.

It will be apparent to the person skilled in the art that there are alarge number of analytical procedures which may be used to detect thepresence or absence of variant nucleotides at one or more positions in agene. In general, the detection of allelic variation requires a mutationdiscrimination technique, optionally an amplification reaction (such asone based on polymerase chain reaction) and optionally a signalgeneration system. There are a multitude of mutation detectiontechniques available in the art and these may be used in combinationwith a signal generation system, of which there are numerous availablein the art. Many methods for the detection of allelic variation arereviewed by Nollau et al., Clin. Chem., 1997, 43, 1114-1120; Anderson SM. Expert Rev Mol Diagn., 2011, 11, 635-642; Meyerson M. et al., Nat RevGenet., 2010, 11, 685-696; and in standard textbooks, for example“Laboratory Protocols for Mutation Detection”, Ed. by U. Landegren,Oxford University Press, 1996 and “PCR”, 2^(nd) Edition by Newton &Graham, BIOS Scientific Publishers Limited, 1997.

As noted above, determining the presence or absence of a particularvariance or plurality of variances in the KRAS gene in a patient withcancer can be performed in a variety of ways. Such tests are commonlyperformed using DNA or RNA collected from biological samples, e.g.,tissue biopsies, urine, stool, sputum, blood, cells, tissue scrapings,breast aspirates or other cellular materials, and can be performed by avariety of methods including, but not limited to, PCR, hybridizationwith allele-specific probes, enzymatic mutation detection, chemicalcleavage of mismatches, mass spectrometry or DNA sequencing, includingminisequencing.

Suitable mutation detection techniques include amplification refractorymutation system (ARMS™), amplification refractory mutation system linearextension (ALEX™), competitive oligonucleotide priming system (COPS),Taqman, Molecular Beacons, restriction fragment length polymorphism(RFLP), and restriction site based PCR and fluorescence resonance energytransfer (FRET) techniques.

In particular embodiments the method employed for determining thenucleotide(s) within a biomarker gene is selected from: allele-specificamplification (allele specific PCR)—such as amplification refractorymutation system (ARMS), sequencing, allelic discrimination assay,hybridisation, restriction fragment length polymorphism (RFLP) oroligonucleotide ligation assay (OLA).

Generation of nucleic acids for analysis from samples generally requiresnucleic acid amplification. Many amplification methods rely on anenzymatic chain reaction (such as a polymerase chain reaction, a ligasechain reaction, or a self-sustained sequence replication) or from thereplication of all or part of the vector into which it has been cloned.Preferably, the amplification according to the present disclosure is anexponential amplification, as exhibited by for example the polymerasechain reaction.

Many target and signal amplification methods have been described in theliterature, for example, general reviews of these methods in Landegren,U., et al., Science, 1988 242, 229-237 and Lewis, R., GeneticEngineering News 1990, 10, 54-55. These amplification methods can beused in the methods of the present disclosure, and include polymerasechain reaction (PCR), PCR in situ, ligase amplification reaction (LAR),ligase hybridisation, Q3 bacteriophage replicase, transcription-basedamplification system (TAS), genomic amplification with transcriptsequencing (GAWTS), nucleic acid sequence-based amplification (NASBA)and in situ hybridisation. Primers suitable for use in variousamplification techniques can be prepared according to methods known inthe art.

Polymerase Chain Reaction (PCR) PCR is a nucleic acid amplificationmethod described inter alia in U.S. Pat. Nos. 4,683,195 and 4,683,202.PCR consists of repeated cycles of DNA polymerase generated primerextension reactions. The target DNA is heat denatured and twooligonucleotides, which bracket the target sequence on opposite strandsof the DNA to be amplified, are hybridised. These oligonucleotidesbecome primers for use with DNA polymerase. The DNA is copied by primerextension to make a second copy of both strands. By repeating the cycleof heat denaturation, primer hybridisation and extension, the target DNAcan be amplified a million fold or more in about two to four hours. PCRis a molecular biology tool, which must be used in conjunction with adetection technique to determine the results of amplification. Anadvantage of PCR is that it increases sensitivity by amplifying theamount of target DNA by 1 million to 1 billion fold in approximately 4hours. PCR can be used to amplify any known nucleic acid in a diagnosticcontext (Mok et al., Gynaecologic Oncology, 1994, 52: 247-252,).

An allele specific amplification technique such as AmplificationRefractory Mutation System (ARMS™) (Newton et al., Nucleic Acids Res.,1989, 17, 2503-2516) can also be used to detect single base mutations.Under the appropriate PCR amplification conditions a single basemismatch located at the 3′-end of the primer is sufficient forpreferential amplification of the perfectly matched allele (Newton etal., 1989, supra), allowing the discrimination of closely relatedspecies. The basis of an amplification system using the primersdescribed above is that oligonucleotides with a mismatched 3′-residuewill not function as primers in the PCR under appropriate conditions.This amplification system allows genotyping solely by inspection ofreaction mixtures after agarose gel electrophoresis.

Analysis of amplification products can be performed using any methodcapable of separating the amplification products according to theirsize, including automated and manual gel electrophoresis, massspectrometry, and the like.

The methods of nucleic acid isolation, amplification and analysis areroutine for one skilled in the art and examples of protocols can befound, for example, Green & Sambrook, Eds., Molecular Cloning: ALaboratory Manual, (2012, 4th edition, Vol. 1-3, ISBN 9781936113422),Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.)Particularly useful protocol source for methods used in PCRamplification is PCR (Basics: From Background to Bench) by M. J.McPherson, S. G. Mailer, R. Beynon, C. Howe, Springer Verlag; 1stedition (Oct. 15, 2000), ISBN: 0387916008.

According to another aspect of the present disclosure there is providedthe use of a compound of Formula (I) to treat a cancer patient whosetumour cells have been identified as possessing a mutant KRAS gene.

According to another aspect of the present disclosure there is provideda compound of Formula (I) for treating cancers with tumour cellsidentified as harbouring mutant KRAS gene.

In still further embodiments, the present disclosure relates topharmaceutical composition comprising a compound of Formula (I) for usein the prevention and treatment of cancer with tumour cells identifiedas harbouring a mutant KRAS gene.

For all the aspects above, mutant forms of KRAS determined/identifiedare at all positions across the gene.

In further aspects, compounds of the present disclosure may also beuseful in treating BRAF mutant cancers. The information provided abovewithin this personalised Healthcare section for KRAS mutant cancers mayanalogously be applied to BRAF resistant cancers, other than Gene BankAccession details. BRAF gene bank accession details: BRAF NM_004333.

DESCRIPTION OF FIGURES

FIG. 1 shows the X-Ray Powder Diffraction Pattern of(R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct Form 1 (Example 18a).

FIG. 2 shows the DSC Thermogram of(R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct Form 1 (Example 18a).

FIG. 3 shows the X-Ray Powder Diffraction Pattern of(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct Form 1 (Example 34).

FIG. 4 shows the DSC Thermogram of(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct Form 1 (Example 34).

FIG. 5 shows Tumour Growth Inhibition by Example 18a in combination withselumetinib (ARRY-142886) in A549 xenograft model.

FIG. 6: Cell Growth Inhibition in KRAS-mutant Non-Small Cell Lung Cancer(NSCLC) A549 cell line by Example 18 in combination with selumetinib(ARRY-142886). Dose matrix representing percent growth inhibition valuestaken from the fitted dose response curves.

FIG. 7: Cell Growth Inhibition in KRAS-mutant Non-Small Cell Lung Cancer(NSCLC) A549 cell line by Example 18 in combination with selumetinib(ARRY-142886). Loewe model of additivity calculated from the monotherapydose response curves.

FIG. 8: Cell Growth Inhibition in KRAS-mutant Non-Small Cell Lung Cancer(NSCLC) A549 cell line by Example 18 in combination with selumetinib(ARRY-142886). Excess heatmap (synergy) calculated by subtracting theLoewe model of additivity data from the fitted data.

FIG. 9: Cell Growth Inhibition in KRAS-mutant Non-Small Cell Lung Cancer(NSCLC) H2122 cell line by Example 18 in combination with selumetinib(ARRY-142886). Dose matrix representing percent growth inhibition valuestaken from the fitted dose response curves.

FIG. 10: Cell Growth Inhibition in KRAS-mutant Non-Small Cell LungCancer (NSCLC) H2122 cell line by Example 18 in combination withselumetinib (ARRY-142886). Loewe model of additivity calculated from themonotherapy dose response curves.

FIG. 11: Cell Growth Inhibition in KRAS-mutant Non-Small Cell LungCancer (NSCLC) H2122 cell line by Example 18 in combination withselumetinib (ARRY-142886). Excess heatmap (synergy) calculated bysubtracting the Loewe model of additivity data from the fitted data.

FIG. 12: Cell Growth Inhibition in KRAS-mutant Non-Small Cell LungCancer (NSCLC) H2009 cell line by Example 18 in combination withselumetinib (ARRY-142886). Dose matrix representing percent growthinhibition values taken from the fitted dose response curves.

FIG. 13: Cell Growth Inhibition in KRAS-mutant Non-Small Cell LungCancer (NSCLC) H2009 cell line by Example 18 in combination withselumetinib (ARRY-142886). Loewe model of additivity calculated from themonotherapy dose response curves.

FIG. 14: Cell Growth Inhibition in KRAS-mutant Non-Small Cell LungCancer (NSCLC) H2009 cell line by Example 18 in combination withselumetinib (ARRY-142886). Excess heatmap (synergy) calculated bysubtracting the Loewe model of additivity data from the fitted data.

FIG. 15: Cell Growth Inhibition in KRAS-mutant Non-Small Cell LungCancer (NSCLC) Calu6 cell line by Example 18 in combination withselumetinib (ARRY-142886). Dose matrix representing percent growthinhibition values taken from the fitted dose response curves.

FIG. 16: Cell Growth Inhibition in KRAS-mutant Non-Small Cell LungCancer (NSCLC) Calu6 cell line by Example 18 in combination withselumetinib (ARRY-142886). Loewe model of additivity calculated from themonotherapy dose response curves.

FIG. 17: Cell Growth Inhibition in KRAS-mutant Non-Small Cell LungCancer (NSCLC) Calu6 cell line by Example 18 in combination withselumetinib (ARRY-142886). Excess heatmap (synergy) calculated bysubtracting the Loewe model of additivity data from the fitted data.

EXAMPLES

The present disclosure will now be illustrated in the following Examplesin which, generally:

-   -   (i) operations were carried out at ambient temperature, i.e. in        the range 17 to 25° C. and under an atmosphere of an inert gas        such as nitrogen unless otherwise stated;    -   (ii) evaporations were carried out by rotary evaporation or        utilising Genevac equipment or Biotage v10 evaporator in vacuo        and work-up procedures were carried out after removal of        residual solids by filtration;    -   (iii) flash chromatography purifications were performed on an        automated Teledyne Isco CombiFlash® Rf or Teledyne Isco        CombiFlash® Companion® using prepacked RediSep Rf Gold™ Silica        Columns (20-40 m, spherical particles), GraceResolv™ Cartridges        (Davisil® silica) or Silicycle cartridges (40-63 μm).    -   (iv) preparative chromatography was performed on a Gilson prep        HPLC instrument with UV collection;    -   (v) chiral preparative chromatography was performed on a Gilson        instrument with UV collection (233 injector/fraction collector,        333 & 334 pumps, 155 UV detector), or an Interchim PuriFlash        4250-250 system or a Novasep LC50 system with Knauer K2501 UV        detector;    -   (vi) yields, where present, are not necessarily the maximum        attainable;    -   (vii) in general, the structures of end-products of the Formula        I were confirmed by nuclear magnetic resonance (NMR)        spectroscopy; NMR chemical shift values were measured on the        delta scale [proton magnetic resonance spectra were determined        using a Bruker Avance 500 (500 MHz) or Bruker Avance 400 (400        MHz) instrument]; measurements were taken at ambient temperature        unless otherwise specified; the following abbreviations have        been used: s, singlet; d, doublet; t, triplet; q, quartet; m,        multiplet; dd, doublet of doublets; ddd, doublet of doublet of        doublet; dt, doublet of triplets; bs, broad signal; where “DMSO”        is referred to as a solvent used in NMR it is understood to be        d6-DMSO;    -   (viii) in general, end-products of the Formula I were also        characterised by mass spectroscopy following liquid        chromatography (LCMS or UPLC); UPLC was carried out using a        Waters UPLC fitted with Waters SQ mass spectrometer (Column temp        40, UV=220-300 nm, Mass Spec=ESI with positive/negative        switching) at a flow rate of lml/min using a solvent system of        97% A+3% B to 3% A to 97% B over 1.50 mins (total runtime with        equilibration back to starting conditions etc 1.70 min), where        A=0.1% formic acid in water (for acid work) or 0.1% ammonia in        water (for base work) B=acetonitrile. For acid analysis the        column used was Waters Acquity HSS T3 1.8 μm 2.1×50 mm, for base        analysis the column used was Waters Acquity BEH 1.7 μm 2.1×50        mm; LCMS was carried out using a Waters Alliance HT (2795)        fitted with a Waters ZQ ESCi mass spectrometer and a Phenomenex        Gemini—NX (50×2.1 mm 5 μm) column at a flow rate of 1.1 ml/min        95% A to 95% B over 4 min with a 0.5 min hold. The modifier is        kept at a constant 5% C (50:50 acetonitrile:water 0.1% formic        acid) or D (50:50 acetonitrile:water 0.1% ammonium hydroxide        (0.88 SG) depending on whether it is an acidic or basic method.    -   (ix) ion exchange purification was generally performed using a        SCX-2 (Biotage, Propylsulfonic acid functionalized silica.        Manufactured using a trifunctional silane. Non end-capped)        cartridge.    -   (x) intermediate purity was assessed by thin layer        chromatographic, mass spectral, HPLC (high performance liquid        chromatography) and/or NMR analysis.    -   (xi) X-Ray Powder Diffraction was performed using a Bruker D4.        The X-ray powder diffractogram was determined by mounting a        sample of the crystalline material on a Bruker single silicon        crystal (SSC) wafer mount and spreading out the sample into a        thin layer with the aid of a microscope slide. The sample was        spun at 30 revolutions per minute (to improve counting        statistics) and irradiated with X-rays generated by a copper        long-fine focus tube operated at 40 kV and 40 mA with a        wavelength of 1.5418 angstroms. The collimated X-ray source was        passed through an automatic variable divergence slit set at V20        and the reflected radiation directed through a 5.89 mm anti        scatter slit and a 9.55 mm detector slit. Samples were measured        in reflection geometry in θ−2θ configuration over the scan range        2° to 40°2θ with a nominal 0.12 second exposure per 0.02°        increment. The instrument was equipped with a Position sensitive        detector (Lynxeye). Persons skilled in the art of X-ray powder        diffraction will understand that the relative intensity of peaks        can be affected by, for example, grains above 30 microns in size        and non-unitary aspect ratios that may affect analysis of        samples. The skilled person will also understand that the        position of reflections can be affected by the precise height at        which the sample sits in the diffractometer and the zero        calibration of the diffractometer. The surface planarity of the        sample may also have a small effect. Hence the diffraction        pattern data presented are not to be taken as absolute values.    -   (xii) Differential Scanning Calorimetry (DSC) was performed        using a TA Instruments Q2000 DSC. Typically less than 5 mg of        material contained in a standard aluminium pan fitted with a lid        was heated over the temperature range 25° C. to 300° C. at a        constant heating rate of 10° C. per minute. A purge gas using        nitrogen was used—flow rate 50 ml per minute.    -   (xiii) the following abbreviations have been used:—

-   2^(nd) Generation XantPhos precatalyst    Chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II)

-   18-crown-6 1,4,7,10,13,16-hexaoxacyclooctadecane

-   aq. Aqueous

-   atm a unit of atmospheric pressure

-   Boc tert-Butoxycarbonyl

-   BrettPhos 3rd generation precatalyst    [2-(di-1-adamantylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl][2-(2′-amino-1,1′-biphenyl)]palladium(II)    methanesulfonate

-   CDCl₃ deutero-chloroform

-   DAST (diethylamino)sulfur trifluoride

-   DCM dichloromethane

-   DIEA N,N-diisopropyl ethylamine

-   DIPEA diisopropylethylamine

-   DMF dim ethyl formamide

-   DMSO dimethyl sulphoxide

-   DSC differential scanning calorimetry

-   EtOH ethanol

-   EtOAc ethyl acetate

-   IPA iso-propylalcohol

-   MeOH methanol

-   MeTHF rac-2-methyltetrahydrofuran

-   NBS N-bromosuccinimide

-   Pd₂dba₃ tris(dibenzylideneacetone)dipalladium(0)

-   rt/RT room temperature

-   sat. Saturated

-   SEM-Cl 2-(Trimethylsilyl)ethoxymethyl chloride

-   TEA triethylamine

-   THF tetrahydrofuran

-   Tos tosyl

-   XPhos 2nd generation precatalyst    Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

-   XRPD X-Ray Powder Diffraction

Example 12-(2-((1-Methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-methylpyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

NaH (12.05 mg, 0.50 mmol) was added to7-((6-methylpyridin-2-yl)methyl)-2-(2-(methylsulfonyl)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 1; 100 mg, 0.25 mmol) andN-(1-methyl-1H-pyrazol-5-yl)formamide (Intermediate 2; 94 mg, 0.75 mmol)in THF (1.5 mL) at 25° C. under nitrogen. The resulting solution wasstirred at 25° C. for 3 hours. EtOH (2 mL) was added, and stirred for 10min. The reaction mixture was quenched with water (50 mL) and extractedinto EtOAc (30×25 mL), the organic layer was dried over Na₂SO₄, filteredand evaporated to afford crude product. The crude product was purifiedby preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mmdiameter, 100 mm length), using decreasingly polar mixtures of water(containing 0.1% NH₄HCO₃) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-methylpyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 1; 40 mg, 38%) as a white solid. ¹HNMR (300 MHz, DMSO, 26° C.)δ 2.51 (3H, s), 3.70 (3H, s), 3.84-3.88 (2H, m), 4.40-4.44 (2H, m), 4.76(2H, s), 6.30 (1H, s), 7.14-7.18 (2H, m), 7.32-7.35 (2H, m), 7.64-7.69(1H, m), 7.93 (1H, s), 8.46 (1H, d), 9.38 (1H, s). m/z (ES+),[M+H]+=416.

Intermediate 17-((6-Methylpyridin-2-yl)methyl)-2-(2-(methylsulfonyl)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

Potassium persulfate (1.01 g, 3.75 mmol) was added portionwise to7-((6-methylpyridin-2-yl)methyl)-2-(2-(methylthio)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 3; 275 mg, 0.75 mmol) in MeOH (5 mL) at 25° C. undernitrogen. The resulting mixture was stirred at 25° C. for 12 hours. Thereaction was then heated to 40° C. and stirred for a further 6 hours.The reaction mixture was then diluted with DCM (100 mL), and washed withwater (25 mL×2). The organic layer was dried over Na₂SO₄, filtered andevaporated to afford crude product. The crude product was purified byflash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Purefractions were evaporated to dryness to afford7-((6-methylpyridin-2-yl)methyl)-2-(2-(methylsulfonyl)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 1; 210 mg, 70%) as a white solid. ¹HNMR (300 MHz, DMSO,26° C.) δ 2.50 (3H, s), 3.46 (3H, s), 3.85-3.95 (2H, m), 4.42-4.46 (2H,m), 4.86 (2H, s), 7.15-7.20 (2H, m), 7.64-7.69 (1H, m), 8.15 (1H, d),8.40 (1H, s), 9.05 (1H, d). m/z (ES+), [M+H]+=399.

Intermediate 2 N-(1-Methyl-1H-pyrazol-5-yl)formamide

Formic acid (3.1 mL, 67.35 mmol) was added to acetic anhydride (7.7 mL,75.42 mmol) to give a colourless solution. The resulting solution wasstirred at 45° C. for 45 minutes. The reaction mixture was then cooledto 0° C. and 1-methyl-1H-pyrazol-5-amine (2 g, 20.59 mmol) was added.The resulting solution was stirred at 0° C. for 10 minutes. The reactionmixture was then poured into a mixture of water (50 mL) and EtOAc (50mL) and the reaction mixture was adjusted to pH 8 with saturated K₂CO₃.The aqueous layer was extracted with EtOAc (6×50 mL) and washed withwater (2×50 mL). The combined organic phases were dried over Na₂SO₄,filtered and evaporated to afford desired productN-(1-methyl-1H-pyrazol-5-yl)formamide (Intermediate 2; 1.21 g, 47%) aswhite solid. ¹H-NMR (300 MHz, CDCl₃, 26° C.) 3.80 (3H, s), 6.11 (1H, s),7.44 (2H, s), 8.35 (1H, s). m/z (ES+), [M+H]+=126.

Intermediate 37-((6-Methylpyridin-2-yl)methyl)-2-(2-(methylthio)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

4-Tributylstannyl-2-thiomethylpyrimidine (2.66 g, 6.41 mmol) was addedto2-bromo-7-((6-methylpyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 4; 1.87 g, 5.82 mmol) and Pd-118([1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II))(0.204 g, 0.29 mmol) in DMF (5 mL) under nitrogen. The resultingsolution was stirred at 150° C. in a microwave reactor for 8 hours. Thereaction mixture was filtered through celite, diluted with EtOAc (200mL), and washed sequentially with water (50 mL×2). The combined organiclayers were dried over Na₂SO₄, filtered and evaporated to afford crudeproduct. The crude product was purified by C18-flash chromatography,elution gradient 0 to 50% MeCN in water. Pure fractions were evaporatedto dryness to afford7-((6-methylpyridin-2-yl)methyl)-2-(2-(methylthio)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 3; 0.28 g, 13%) as a grey solid. ¹H-NMR (400 MHz, CDCl₃,22° C.) δ 2.50 (3H, s), 2.63 (3H, s), 3.85-3.89 (2H, m), 4.39-4.43 (2H,m), 4.85 (2H, s), 7.15-7.19 (2H, m), 7.59-7.69 (2H, m), 8.23 (1H, s),8.63 (1H, d). m/z (ES+), [M+H]+=367.

Intermediate 42-Bromo-7-((6-methylpyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

Sodium acetate (3.24 g, 39.6 mmol) was added portionwise to ethyl1-(2-aminoethyl)-4-bromo-1H-imidazole-2-carboxylate dihydrochloride(Intermediate 5; 5.3 g, 15.8 mmol) and 6-Methyl-2-pyridinecarboxaldehyde(1.92 g, 15.8 mmol) in MeOH (100 mL) cooled to 0° C. under nitrogen. Theresulting solution was then stirred at 0° C. for 15 minutes. Sodiumtriacetoxyborohydride (10.1 g, 47.5 mmol) was added potionwise at 0° C.and the resulting solution was stirred at room temperature for 12 hours.The reaction mixture was then adjusted to pH 7-8 with saturated NaHCO₃and diluted with DCM (250 mL). The DCM phase was then washedsequentially with water (50 mL×2). The combined organic phases weredried over Na₂SO₄, filtered and evaporated to afford crude product. Thecrude product was purified by flash silica chromatography, elutiongradient 0 to 9% MeOH in DCM. Pure fractions were evaporated to drynessto afford2-bromo-7-((6-methylpyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 4; 2.5 g, 49%) as a white solid. ¹H-NMR (300 MHz, DMSO,27° C.) δ 2.44 (3H, s), 3.80-3.84 (2H, m), 4.28-4.32 (2H, m) 4.73 (2H,s), 7.13-7.16 (2H, m), 7.63-7.68 (1H, m), 7.96 (1H, s). m/z (ES+),[M+H]+=321.

Intermediate 5 Ethyl 1-(2-aminoethyl)-4-bromo-1H-imidazole-2-carboxylatedihydrochloride

Ethyl4-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-imidazole-2-carboxylate(Intermediate 6; 4.6 g, 12.70 mmol) was added to HCl (excess) in1,4-dioxane (40 mL) and the resulting solution stirred at roomtemperature for 2 hours. The solvent was removed under reduced pressureand the resulting solid was titrated with heptane and filtered to affordethyl 1-(2-aminoethyl)-4-bromo-1H-imidazole-2-carboxylate (Intermediate5; 5.30 g, 140%) as white solid. ¹H-NMR (300 MHz, DMSO, 25° C.) δ 1.33(3H, t), 3.03-3.16 (2H, m), 4.35 (2H, q), 4.63 (2H, t), 7.34 (1H, s).

Intermediate 6 Ethyl4-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-imidazole-2-carboxylate

NBS (10.05 g, 56.5 mmol) was added portionwise to ethyl1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-imidazole-2-carboxylate(Intermediate 7; 16 g, 56.5 mmol) in DCM (80 mL) and DMF (80 mL) at 0°C. under nitrogen. The resulting solution was then stirred at 0° C.temperature for 12 hours. The reaction mixture was diluted with DCM (300mL), and washed sequentially with water (100 mL×2). The organic layerwas dried over Na₂SO₄, filtered and evaporated to afford crude product.The crude product was purified by flash silica chromatography, elutiongradient 0 to 20% EtOAc in DCM. Pure fractions were evaporated todryness to afford ethyl4-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-imidazole-2-carboxylate(Intermediate 6; 4.60 g, 22.49%) as a white solid. ¹H-NMR (300 MHz,DMSO, 27° C.) δ 1.39-1.44 (12H, m), 3.47-3.53 (2H, m), 4.37-4.44 (2H,q), 4.53 (1H, s), 7.04 (1H, s). m/z (ES+), [M+H]+=362.

Intermediate 7 Ethyl1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-imidazole-2-carboxylate

tert-Butyl (2-bromoethyl)carbamate (17.59 g, 78.49 mmol) was added toethyl 1H-imidazole-2-carboxylate (10 g, 71.36 mmol) and K₂CO₃ (11.83 g,85.63 mmol) in DMF (200 mL) under nitrogen and the resulting mixturestirred at 80° C. for 8 hours. The reaction mixture was diluted withEtOAc (300 mL), and washed sequentially with water (50 mL×2). Theaqueous layer was then further extracted with EtOAc (50 mL×5). Thecombined organic phases were dried over MgSO₄, filtered and evaporatedto afford crude product. The crude product was purified by flash silicachromatography, elution gradient 0 to 100% EtOAc in petroleum ether.Pure fractions were evaporated to dryness to afford ethyl1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-imidazole-2-carboxylate(Intermediate 7; 10.7 g, 53%) as a colourless liquid. ¹HNMR (400 MHz,DMSO, 21° C.) δ 1.20 (3H, t), 1.29 (9H, s), 3.26-3.34 (2H, m) 4.27 (2H,q), 4.32-4.40 (2H, m), 6.90 (1H, s), 7.06 (1H, s), 7.32 (1H, s).

Example 2(S)-7-(3-Chlorobenzyl)-6-methyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

(S)-7-(3-Chlorobenzyl)-2-(2-chloropyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 8; 216 mg, 0.56 mmol), 1-methyl-1H-pyrazol-5-amine (59.4mg, 0.61 mmol), cesium carbonate (363 mg, 1.11 mmol) and BrettPhos 3rdgeneration pre-catalyst (25.2 mg, 0.03 mmol) were suspended intert-butanol (8 mL) and de-gassed with nitrogen for 10 minutes. Thereaction was heated to 80° C. for 2 days under nitrogen. The reactionwas then allowed to cool to room temperature, diluted with ethyl acetate(100 mL) and washed with saturated aqueous sodium bicarbonate (25 mL).The organic phases were dried over Na₂SO₄ and concentrated in vacuo togive a brown solid (250 mg). The solid was taken up in DMSO (5 mL) andfiltered. The DMSO solution of crude product was then purified bypreparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mmdiameter, 100 mm length), using decreasingly polar mixtures of water(containing 1% NH₃) and MeCN as eluents. Solvent was removed from thefractions containing product and the solid was dissolved in a mixture ofDCM and methanol, then absorbed onto silica gel. The crude product wasthen purified by flash silica chromatography, elution gradient 0 to 15%MeOH in EtOAc. Pure fractions were evaporated to dryness to afford(S)-7-(3-chlorobenzyl)-6-methyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 2; 43 mg, 17.22%) as a white solid. ¹H NMR (400 MHz, DMSO, 30°C.) 1.13 (3H, d), 3.71 (3H, s), 3.95-4.02 (1H, m), 4.28-4.45 (3H, m),5.07 (1H, d), 6.31 (1H, d), 7.32-7.43 (5H, m), 7.46 (1H, s), 7.92 (1H,s), 8.48 (1H, d), 9.33 (1H, s). m/z: ES+[M+H]+ 449.

Intermediate 8(S)-7-(3-Chlorobenzyl)-2-(2-chloropyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

Sodium hydride (60% dispersion) (25.03 mg, 0.63 mmol) was added to(S)-2-(2-chloropyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 9; 150 mg, 0.57 mmol) in DMF (12 mL) under nitrogen. Theresulting suspension was stirred at 20° C. for 30 minutes.3-Chlorobenzyl chloride (101 mg, 0.63 mmol) was added followed bytetrabutylammonium iodide (42.0 mg, 0.11 mmol) and the resultingsolution stirred at 20° C. for 18 hours. The reaction mixture was pouredinto saturated aqueous NH₄Cl (25 mL) and the aqueous phase extractedwith EtOAc (75 mL). The organic phases were dried over Na₂SO₄ andconcentrated in vacuo to give(S)-7-(3-chlorobenzyl)-2-(2-chloropyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 8; 221 mg, 100%) as a light brown solid. ¹H NMR (400 MHz,DMSO, 21° C.) 1.13 (3H, d), 4.00 (1H, td), 4.27 (1H, dd), 4.38 (1H, d),4.46 (1H, dd), 5.07 (1H, d), 7.36-7.4 (2H, m), 7.41 (1H, dd), 7.47 (1H,s), 7.93 (1H, d), 8.27 (1H, s), 8.75 (1H, d). m/z: ES+ [M+H]+ 388.

Intermediate 9(S)-2-(2-Chloropyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

A mixture of (S)-ethyl1-(2-aminopropyl)-4-(2-chloropyrimidin-4-yl)-1H-imidazole-2-carboxylate.HCl(Intermediate 10; 2.16 g, 6.24 mmol) and 7N ammonia in methanol (107 ml,748.7 mmol) was stirred under nitrogen at room temperature for 1 hour.The volatiles were removed under reduced pressure and the resultingsolid was triturated with diethylether and DCM to afford an off whitesolid. The solid was further triturated with water and washed withdiethylether and then absorbed on to silica from a DCM/methanol mixture.The crude product was purified by silica gel chromatography, elutingwith 0-10% methanol in DCM. Pure fractions were combined and evaporatedto afford a white solid, this was triturated with diethylether to afford(S)-2-(2-chloropyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 9; 0.6 g, 37%) as a white solid. ¹H NMR (400 MHz, DMSO,30° C.) 1.22 (3H, d), 3.93-4.08 (2H, m), 4.39 (1H, d), 7.89 (1H, d),8.23 (1H, s), 8.36 (1H, s), 8.73 (1H, d). m/z: ES+ [M+H]+ 264.

Intermediate 10 (S)-Ethyl1-(2-aminopropyl)-4-(2-chloropyrimidin-4-yl)-1H-imidazole-2-carboxylatehydrochloride

To a solution of (S)-ethyl1-(2-((tert-butoxycarbonyl)amino)propyl)-4-(2-chloropyrimidin-4-yl)-1H-imidazole-2-carboxylate(Intermediate 11; 2.56 g, 6.25 mmol) in 1,4-dioxane (50 mL) was addedHCl (4N in 1,4-dioxane, 39 mL, 156.2 mmol) and reaction stirred atambient temperature for 2 hours. The volatiles were removed underreduced pressure to afford (S)-ethyl1-(2-aminopropyl)-4-(2-chloropyrimidin-4-yl)-1H-imidazole-2-carboxylate.HCl(Intermediate 10; 2.16 g) as a gum which was taken into the preparationof Intermediate 9 without further purification. m/z: ES+ [M+H]+ 310.

Intermediate 11 (S)-Ethyl1-(2-((tert-butoxycarbonyl)amino)propyl)-4-(2-chloropyrimidin-4-yl)-1H-imidazole-2-carboxylate

K₂CO₃ (4.32 g, 31.3 mmol) was added to (S)-tert-butyl4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (Intermediate12; 2.23 g, 9.38 mmol), ethyl4-(2-chloropyrimidin-4-yl)-1H-imidazole-2-carboxylate (Intermediate 14;1.58 g, 6.25 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (0.413 g,1.56 mmol) in 1,4-dioxane (50 mL) at 22° C. under nitrogen. Theresulting mixture was stirred at 100° C. for 3 hours. Evaporation of theorganic phase afforded a gum, which was suspended in dichloromethane andextracted with water and dried by passing through a phase separatorcartridge. Evaporation afforded (S)-ethyl1-(2-((tert-butoxycarbonyl)amino)propyl)-4-(2-chloropyrimidin-4-yl)-1H-imidazole-2-carboxylate(Intermediate 11; 2.56 g, 100%) as a solid. m/z: ES+ [M+H]+ 410.

Intermediate 12 (4S)-tert-Butyl4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

Ruthenium(III) chloride hydrate (0.062 g, 0.28 mmol) was added to astirred mixture of tert-butyl(4S)-4-methyl-2-oxido-oxathiazolidin-2-ium-3-carboxylate (Intermediate13; 87.36 g, 394.80 mmol) in acetonitrile (778 mL) and water (419 mL) at15° C., followed by portionwise addition of sodium periodate (93 g,434.29 mmol). The biphasic mixture was stirred at 20° C. for 1 hour.Water (600 mL) was added and the mixture extracted into ethyl acetate(3×600 mL). The combined organics were washed with water (500 mL), brine(250 mL), dried over MgSO₄, filtered and concentrated in vacuo to give(S)-tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(Intermediate 12; 84.3 g, 355 mmol, 90%) as an off-white solid. ¹H NMR(400 MHz, CDCl₃, 30° C.) 1.51 (3H, d), 1.55 (9H, s), 4.19 (1H, dd),4.37-4.46 (1H, m), 4.66 (1H, dd).

Intermediate 13 tert-Butyl(4S)-4-methyl-2-oxido-oxathiazolidin-2-ium-3-carboxylate

To a solution of 1H-imidazole (106 g, 1553.20 mmol) and triethylamine(124 mL, 893.09 mmol) in anhydrous dichloromethane (1427 mL) at −55° C.was added thionyl chloride (32.6 mL, 446.54 mmol) dropwise (exothermic,keeping T<−40° C.). The mixture was stirred for 5 minutes while coolingto −60° C. and a solution of (S)-tert-butyl1-hydroxypropan-2-ylcarbamate (Sigma-Aldrich; 68.04 g, 388.30 mmol) inanhydrous dichloromethane (1427 mL) was added dropwise over 3.5 hoursvia a dropping funnel. The reaction mixture was stirred while warming toroom temperature overnight. Water was added (750 mL) and the phasesseparated. The aqueous was further extracted into dichloromethane (500mL). The combined organics were washed with water (250 mL), saturatedbrine (250 mL), dried over MgSO₄, filtered and concentrated in vacuo togive tert-butyl (4S)-4-methyl-2-oxido-oxathiazolidin-2-ium-3-carboxylate(Intermediate 13; 87.3 g, 395 mmol, 100%) as a pale oil. ¹H NMR (400MHz, CDCl₃, 30° C.) 1.50 (3H, d), 4.29 (1H, d), 4.68 (1H, t), 4.77 (1H,dd).

Intermediate 14 Ethyl4-(2-chloropyrimidin-4-yl)-1H-imidazole-2-carboxylate

XPhos 2nd generation precatalyst (0.435 g, 0.55 mmol) was added to adegassed solution of ethyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (Intermediate 15; 3.86g, 11.05 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (4.21 g,16.58 mmol) and KOAc (2.17 g, 22.10 mmol) in dioxane (100 mL) at ambienttemperature under nitrogen and the resulting solution was heated to 85°C. for 3 hours. The reaction mixture was allowed to cool to 50° C. andcesium carbonate (7.20 g, 22.10 mmol), 2,4-dichloropyrimidine (1.646 g,11.05 mmol) and water (20 mL) were added followed by Pd(PPh₃)₄(0.638 g,0.55 mmol) and the reaction mixture heated at 85° C. for 2 hours. Thereaction mixture was then passed through celite and washed with MeOH andthe volatiles removed under reduced pressure. Water and DCM were addedand organic layer extracted and dried by passing through a phaseseparator cartridge. The volatiles were then removed under reducedpressure to afford an impure brown solid ethyl4-(2-chloropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (4.24 g, 11.07 mmol).2,2,2-trifluoroacetic acid (8.48 mL, 110.73 mmol) was added to ethyl4-(2-chloropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate(4.24 g, 11.07 mmol) in DCM (100 mL) and the resulting solution wasstirred at ambient temperature for 2 hours and then left to stand atambient temperature for 16 hours. The volatiles were removed underreduced pressure, the resultant solid was dissolved in DCM and water andfiltered through a layer of celite. The aqueous layer was separated andbasified with saturated sodium bicarbonate and extracted into DCM, thendried by passing through a phase separator cartridge and the solventremoved to afford a solid. The organic layer was passed through a phaseseparator cartridge, combined with the solid and pre-absorbed ontosilica and subjected to silica chromatography eluting with 0-100%diethylether in DCM. Pure fractions were combined and evaporated toafford ethyl 4-(2-chloropyrimidin-4-yl)-1H-imidazole-2-carboxylate(Intermediate 14; 1.58 g, 57%) as a solid. ¹H NMR (400 MHz, DMSO, 30°C.) 1.35 (3H, t), 4.38 (2H, q), 7.93 (1H, d), 8.19 (1H, s), 8.73 (1H,d), 13.95 (1H, s). m/z: ES+ [M+H]+ 253.

Intermediate 15 Ethyl4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate

NBS (26.3 g, 147.93 mmol) was added to ethyl1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate(Intermediate 16; 40 g, 147.93 mmol) in DMF (150 mL) under nitrogen andthe resulting mixture stirred at 25° C. for 20 hours. The reactionmixture was quenched with water (200 mL), extracted with EtOAc (2×300mL), the organic layers were washed with brine and dried over Na₂SO₄,filtered and evaporated to afford a yellow residue. The crude productwas purified by flash silica chromatography, elution gradient 0 to 10%EtOAc in petroleum ether. Pure fractions were evaporated to dryness toafford ethyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (Intermediate 15; 21 g,41%) as a colourless oil which solidified on standing. ¹H NMR (400 MHz,CDCl₃, 25° C.) δ 0.02 (9H, s), 0.92-1.01 (2H, m), 1.45 (3H, t),3.56-3.65 (2H, m), 4.45 (2H, q), 5.79 (2H, s), 7.28 (1H, s). m/z (ES+),[M+H]+=349/351.

Intermediate 16 Ethyl1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate

SEM-Cl (18.98 mL, 107.04 mmol) was added to ethyl1H-imidazole-2-carboxylate (10 g, 71.36 mmol) and NaH (4.28 g, 107 mmol)in DMF (50 mL) at 0° C. under nitrogen. The resulting mixture was thenstirred at 25° C. for 12 hours. The reaction mixture was quenched withwater (50 mL), extracted with EtOAc (2×100 mL), the organic layer wasdried over Na₂SO₄, filtered and evaporated to afford a yellow residue.The crude product was purified by flash silica chromatography, elutiongradient 30 to 70% EtOAc in petroleum ether. Pure fractions wereevaporated to dryness to afford ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (Intermediate 16; 20 g,100%) as a yellow oil. ¹H NMR (400 MHz, DMSO, 30° C.) δ 0.00 (9H, s),0.03-0.08 (2H, m), 1.37 (3H, t), 3.53-3.62 (2H, m), 4.37 (2H, q), 5.76(2H, s), 7.18 (1H, d), 7.68 (1H, d). m/z: ES+ [M+H]+ 271.

Example 3(S)-7-(3-Chloro-4-fluorobenzyl)-6-methyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

(S)-7-(3-Chloro-4-fluorobenzyl)-2-(2-chloropyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 17; 226 mg, 0.56 mmol), 1-methyl-1H-pyrazol-5-amine (59.4mg, 0.61 mmol), cesium carbonate (363 mg, 1.11 mmol) and BrettPhos 3rdgeneration pre-catalyst (25.2 mg, 0.03 mmol) were suspended intert-butanol (8 mL) and de-gassed with nitrogen for 10 minutes. Thereaction was heated to 80° C. for 2 days under nitrogen. The reactionwas then cooled to room temperature, diluted with ethyl acetate (100 mL)and the organic phase was washed with saturated aqueous sodiumbicarbonate (25 mL), dried over Na₂SO₄ and concentrated in vacuo to givea brown gum. This gum was taken up in DMSO (5 mL) and filtered. The DMSOsolution of crude product was then purified by preparative HPLC (WatersXBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length),using decreasingly polar mixtures of water (containing 1% NH₃) and MeCNas eluents. Fractions containing the desired compound were evaporated todryness to afford crude material. This was dissolved in a minimum ofDCM, and absorbed onto silica gel by concentration under reducedpressure. The crude product was then further purified by flash silicachromatography, elution gradient 0 to 15% MeOH in EtOAc. Pure fractionswere evaporated to dryness to afford(S)-7-(3-chloro-4-fluorobenzyl)-6-methyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 3; 40 mg, 15%) as an off white solid. ¹H NMR (400 MHz, DMSO,30° C.) δ 1.13 (3H, d), 3.71 (3H, s), 3.96-4.03 (1H, m), 4.26-4.39 (2H,m), 4.41 (1H, dd), 5.04 (1H, d), 6.30 (1H, d), 7.35 (2H, dd), 7.39-7.44(2H, m), 7.55-7.69 (1H, m), 7.92 (1H, s), 8.48 (1H, d), 9.33 (1H, s).m/z: ES+ [M+H]+ 467.

Intermediate 17(S)-7-(3-Chloro-4-fluorobenzyl)-2-(2-chloropyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

Sodium hydride (60% dispersion, 25 mg, 0.63 mmol) was added to(S)-2-(2-chloropyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 9; 150 mg, 0.57 mmol) in DMF (12 mL) under nitrogen. Theresulting suspension was stirred at 20° C. for 30 minutes.2-Chloro-4-(chloromethyl)-1-fluorobenzene (112 mg, 0.63 mmol) was addedfollowed by tetrabutylammonium iodide (42.0 mg, 0.11 mmol) and theresulting solution stirred at 20° C. for 18 hours. The reaction mixturewas poured into saturated aqueous NH₄Cl (25 mL) and extracted with ethylacetate (75 mL). The organic phases were dried over Na₂SO₄ andconcentrated in vacuo to give(S)-7-(3-chloro-4-fluorobenzyl)-2-(2-chloropyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 17; 230 mg, 100%) as a light brown solid. ¹H NMR (400 MHz,DMSO, 33° C.) δ 1.13 (3H, d), 4.01 (1H, ddd), 4.26 (1H, dd), 4.36 (1H,d), 4.46 (1H, dd), 5.05 (1H, d), 7.39-7.41 (1H, m), 7.42 (1H, s),7.59-7.66 (1H, m), 7.93 (1H, d), 8.27 (1H, s), 8.74 (1H, dd). m/z: ES+[M+H]+ 406.

Example 4(S)-7-(3,4-Difluorobenzyl)-6-methyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

(S)-2-(2-Chloropyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 18; 218 mg, 0.56 mmol), 1-methyl-1H-pyrazol-5-amine (59.7mg, 0.62 mmol), cesium carbonate (364 mg, 1.12 mmol) and BrettPhos 3rdgeneration pre-catalyst (25.3 mg, 0.03 mmol) were suspended intert-butanol (8 mL) and de-gassed with nitrogen for 10 minutes. Thereaction was heated to 80° C. for 18 hours under nitrogen. The reactionwas cooled to room temperature, diluted with ethyl acetate (100 mL) andwashed with saturated aqueous NaHCO₃ (25 mL), dried over Na₂SO₄ andconcentrated in vacuo to give a brown solid. The crude material wasdissolved in DCM, concentrated in vacuo and adsorbed onto silica. Thecrude product was purified by flash silica chromatography, elutiongradient 0 to 15% MeOH in EtOAc. Pure fractions were evaporated todryness to afford(S)-7-(3,4-difluorobenzyl)-6-methyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 4; 88 mg, 34.9%) as an off white solid. ¹H NMR (400 MHz, DMSO,30° C.) δ 1.13 (3H, d), 3.71 (3H, s), 3.96-4.03 (1H, m), 4.27-4.38 (2H,m), 4.43 (1H, dd), 5.05 (1H, d), 6.30 (1H, d), 7.22-7.28 (1H, m), 7.35(2H, dd), 7.37-7.5 (2H, m), 7.92 (1H, s), 8.47 (1H, d), 9.33 (1H, s).m/z: ES+ [M+H]+ 451.

Intermediate 18(S)-2-(2-Chloropyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

Sodium hydride (60% dispersion) (25.03 mg, 0.63 mmol) was added to(S)-2-(2-chloropyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 9; 150 mg, 0.57 mmol) in DMF (12 mL) under nitrogen. Theresulting suspension was stirred at 20° C. for 30 minutes.4-(bromomethyl)-1,2-difluorobenzene (130 mg, 0.63 mmol) was addedfollowed by tetrabutylammonium iodide (42.0 mg, 0.11 mmol) and theresulting solution stirred at 20° C. for 18 hours. The reaction mixturewas poured into saturated aqueous NH₄Cl (25 mL) and extracted with ethylacetate (75 mL). The organic phases were dried over Na₂SO₄ andconcentrated in vacuo to give(S)-2-(2-chloropyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 18; 222 mg, 100%) as a brown gum. ¹H NMR (400 MHz, DMSO,30° C.) δ 1.14 (3H, d), 3.94-4.07 (1H, m), 4.27 (1H, dd), 4.36 (1H, d),4.47 (1H, dd), 5.06 (1H, d), 7.26 (1H, s), 7.37-7.51 (2H, m), 7.93 (1H,d), 8.26 (1H, s), 8.74 (1H, d). m/z: ES+ [M+H]+ 390.

Example 52-(5-Methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

3rd Generation BrettPhos precatalyst (10.72 mg, 0.01 mmol) was added to2-(2-chloro-5-methylpyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 19; 50 mg, 0.12 mmol), 1-methyl-1H-pyrazol-5-amine (22.97mg, 0.24 mmol) and Cs₂CO₃ (96 mg, 0.30 mmol) in 1,4-dioxane (3 mL) at25° C. under nitrogen. The resulting solution was stirred at 120° C. for8 hours. The solvent was removed by distillation under vacuum. The crudeproduct was purified by flash silica chromatography, elution gradient 3to 4% MeOH in DCM. Pure fractions were evaporated to dryness to affordcrude product. The crude product was further purified by preparativeHPLC (XSelect CSH Prep C18 OBD column, 5 silica, 19 mm diameter, 150 mmlength), using decreasingly polar mixtures of water (containing 0.05%NH₄HCO₃) and MeCN as eluents. Fractions containing the desired compoundwere evaporated to dryness to afford2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 5; 23.5 mg, 41%) as a white solid. ¹H NMR (400 MHz, DMSO, 20.1°C.) δ 2.51 (3H, s), 3.70 (3H, s), 3.90-3.98 (2H, m), 4.43-4.51 (2H, m),4.91 (2H, s), 6.31 (1H, d), 7.34 (1H, d), 7.76 (1H, d), 7.84 (1H, d),7.95 (1H, s), 8.10 (1H, t), 8.33 (1H, s), 9.24 (1H, s). m/z (ES+),[M+H]+=484.

Intermediate 192-(2-Chloro-5-methylpyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

NH₃ (7N in MeOH, 3 mL) was added to ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-(2-(((6-(trifluoromethyl)pyridin-2-yl)methyl)amino)ethyl)-1H-imidazole-2-carboxylate(Intermediate 20; 60 mg, 0.13 mmol) at 25° C. under air and theresulting solution was stirred at 50° C. for 12 hours. The solvent wasremoved by distillation under vacuum to afford2-(2-chloro-5-methylpyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 19; 50 mg, 92%) as a white solid. m/z (ES+), [M+H]+=423.

Intermediate 20 Ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-(2-(((6-(trifluoromethyl)pyridin-2-yl)methyl)amino)ethyl)-1H-imidazole-2-carboxylate

6-(trifluoromethyl)picolinaldehyde (114 mg, 0.65 mmol) was added toethyl1-(2-aminoethyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 21; 250 mg, 0.65 mmol) in DCM (10 mL) at25° C. under air. The resulting solution was stirred at 40° C. for 3hours. Sodium triacetoxyborohydride (415 mg, 1.96 mmol) was added toreaction mixture at 25° C. and the resulting solution was stirred at 25°C. for 12 hours. The reaction mixture was quenched with water (10 mL)and extracted with DCM (3×15 mL). The organic layers were combined andwashed with brine (15 mL), dried over Na₂SO₄, filtered and the volatilesremoved under reduced pressure. The crude product was purified by flashsilica chromatography, elution gradient 2 to 5% MeOH in DCM. Purefractions were evaporated to dryness to afford ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-(2-(((6-(trifluoromethyl)pyridin-2-yl)methyl)amino)ethyl)-1H-imidazole-2-carboxylate(Intermediate 20; 60 mg, 19.6%) as a white solid. m/z (ES+), [M+H]+=469.

Intermediate 211-(2-Aminoethyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate.HCl

HCl (4N in 1,4-dioxane, 50 mL) was added to ethyl1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate(Intermediate 22; 3.2 g, 7.81 mmol) at 25° C. under air and theresulting solution was stirred at 25° C. for 12 hours. The solvent wasremoved by distillation under vacuum and the crude residue wastriturated with EtOAc to give a solid which was collected by filtrationand dried under vacuum to give ethyl1-(2-aminoethyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate.HCl(Intermediate 21; 2.90 g, 97%) as a white solid. ¹H NMR (400 MHz, DMSO,20.1° C.) δ 1.35 (3H, t), 2.60-2.65 (3H, m), 4.38 (2H, q), 4.75 (2H, t),8.37 (3H, s), 8.46 (1H, s), 8.63 (1H, d), 10.17 (2H, s). m/z (ES+),[M+H]+=310.

Intermediate 22 Ethyl1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate

tert-Butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (2.76 g,12.37 mmol) was added portionwise to ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate(Intermediate 23; 3.0 g, 11.25 mmol), K₂CO₃ (4.66 g, 33.75 mmol) and18-crown-6 ether (0.595 g, 2.25 mmol) in 1,4-dioxane (60 mL) at 100° C.under air. The resulting solution was stirred at 100° C. for 2 hours.The mixture was cooled, filtered and the resulting solid was washed withethyl acetate. The filtrate was then concentrated under reducedpressure. The crude product was purified by flash silica chromatography,elution gradient 25 to 30% EtOAc in petroleum ether. Pure fractions wereevaporated to dryness to afford ethyl1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate(Intermediate 22; 3.20 g, 69.4%) as a white solid. ¹H NMR (400 MHz,DMSO, 20.2° C.) δ 1.25 (9H, s), 1.35 (3H, t), 2.62 (3H, s), 3.35 (2H,dd), 4.37 (2H, q), 4.49 (2H, t), 6.93 (1H, t), 8.18 (1H, s), 8.61 (1H,s). m/z (ES+), [M+H]+=410.

Intermediate 23 Ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate

Trifluoroacetic acid (20 mL, 259.60 mmol) was added to ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate(Intermediate 24; 5.6 g, 14.11 mmol) in DCM (20 mL) at 25° C. and theresulting mixture was stirred at 25° C. for 12 hours. The volatiles werethen removed under reduced pressure and the reaction mixture wasbasified with saturated NaHCO₃. The resulting precipitate formed wascollected by filtration, washed with water (100 mL) and dried undervacuum to afford ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate(Intermediate 23; 3.50 g, 93%) as a white solid. ¹H NMR (400 MHz, DMSO,23° C.) δ 1.35 (3H, t), 2.62 (3H, s), 4.37 (2H, q), 8.13 (1H, s), 8.62(1H, s), NH not observed. m/z (ES+), [M+H]+=267.

An alternative method for the preparation of Intermediate 23:

Ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate(Intermediate 24; 176 g, 443.38 mmol) was added to TFA (500 mL, 6489.91mmol) in DCM (500 mL). The resulting reaction mixture was stirred atroom temperature for 16 hours. The volatiles were then removed underreduced pressure. Excess saturated aqueous Na₂CO₃ was added and theresulting precipitate was collected by filtration, washed with water (1L) and dried under vacuum. The crude solid was triturated with MeCN togive a solid which was collected by filtration and dried under vacuum togive ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate(Intermediate 23; 106 g, 90%) as a white solid. ¹H NMR (300 MHz, DMSO,19.7° C.) δ 1.34 (3H, t), 2.61 (3H, s), 4.33-4.41 (2H, m), 8.13 (1H, s),8.61 (1H, s), 13.99 (1H, s). m/z (ES+), [M+H]+=267.

An alternative method for one pot synthesis of Intermediate 23:

Step 1:

To a stirred solution of 3,4,7,8-Tetramethyl-1,10-phenanthroline (3.72g, 15.41 mmol) and Di-mu-methoxobis(1,5-cyclooctadiene)diiridium (I)(5.21 g, 7.71 mmol) in anhydrous MeTHF (900 mL) were added successivelybis(pinacolato)diboron (108 g, 423.86 mmol) and a solution of ethyl1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (114.5g, 385.33 mmol) in MeTHF (100 mL) under nitrogen atmosphere. Theresulting mixture was degassed 3 times under nitrogen, heated to 70° C.and stirred for 3 hours. The reaction mixture was quenched with water(25 mL), the organic phase separated and concentrated to 500 mL. Thissolution was used directly in Step 2 without purification.

Step 2:

The MeTHF (500 mL) solution produced in Step 1 was added slowly to astirred mixture of aqueous K₂CO₃ (161 g, 1156 mmol) in water (500 mL),2,4-dichloro-5-methylpyrimidine (77 g, 462.4 mmol) and1,1′-Bis(diphenylphosphino) ferrocene dichloropalladium (II)dichloromethane adduct (9.44 g, 15.56 mmol) in MeTHF (500 mL) at 40° C.over 3 hours. After complete addition, the layers were separated and theorganic layer was washed with water (500 mL) and concentrated to 500 mL.This was used directly in Step 3 without purification.

Step 3:

HCl in iso-propylalcohol (5-6 N, 116 mL, 578 mmol) was a added to thesolution produced in Step 2 at room temperature and stirred for 30minutes. The reaction mixture was then diluted with water (500 mL). Theaqueous layer was extracted with MeTHF (500 mL) and combined organiclayers were washed with aqueous sodium bicarbonate (4% w/w solution, 500mL) and water (200 mL). The organic phase was concentrated to half andstirred with heptane (1000 mL). The resulting precipitate was filtered,washed with a MeTHF/heptane mixture (1:4, 500 mL) and dried under vacuumto afford ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate as asolid (Intermediate 23, 60.5 g, 59%, overall yield over 3 Steps). ¹H NMR(400 MHz, DMSO, 23° C.) δ 1.35 (3H, t), 2.62 (3H, s), 4.37 (2H, q), 8.13(1H, s), 8.62 (1H, s), NH not observed. m/z (ES+), [M+H]+=267.

Intermediate 24 Ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate

Pd(Ph₃P)₄ (1.158 g, 1.00 mmol) was added to(2-(ethoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)boronic acid (Intermediate 25; 6.3g, 20.05 mmol), 2,4-dichloro-5-methylpyrimidine (3.27 g, 20.05 mmol) andCs₂CO₃ (13.07 g, 40.10 mmol) in 1,4-dioxane (120 mL) and water (20 mL)at 25° C. under nitrogen and the resulting mixture was stirred at 85° C.for 2 hours. The reaction mixture was poured into water (200 mL),extracted with DCM (2×250 mL), the organic layer was dried over Na₂SO₄,filtered and evaporated. The crude product was purified by flash silicachromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Purefractions were evaporated to dryness to afford ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (Intermediate 24; 5.60g, 70.4%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃, 23° C.) δ 0.02(9H, s), 0.93-1.03 (2H, m), 1.48 (3H, t), 2.71-2.76 (3H, m), 3.59-3.69(2H, m), 4.48 (2H, q), 5.85 (2H, s), 8.16 (1H, s), 8.42-8.47 (1H, m).m/z (ES+), [M+H]+=397.

An Alternative Method for the Preparation of Intermediate 24:

Batch 1: Pd(Ph₃P)₄ (1.655 g, 1.43 mmol) was added to(2-(ethoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)boronic acid (Intermediate 25; 9g, 28.64 mmol), 2,4-dichloro-5-methylpyrimidine (4.67 g, 28.64 mmol) andCs₂CO₃ (28.0 g, 85.93 mmol) in 1,4-dioxane (80 mL) and water (20 mL)under nitrogen. The reaction mixture was then stirred at 85° C. for 2hour and then cooled to room temperature.

Batch 2: Pd(Ph₃P)₄ (24.82 g, 21.48 mmol) was added to2,4-dichloro-5-methylpyrimidine (70.0 g, 429.64 mmol),(2-(ethoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)boronicacid (Intermediate 25; 135 g, 429.64 mmol) and Cs₂CO₃ (420 g, 1288.91mmol) in 1,4-dioxane (2000 mL) and water (400 mL) under nitrogen. Thereaction mixture was then stirred at 85° C. for 2 hour and then cooledto room temperature.

Batches 1 and 2 above were combined and evaporated to dryness. Theresidue was dissolved in EtOAc (2 L) and washed sequentially withsaturated aqueous NaHCO₃ (450 mL), water (300 mL) and brine (350 mL).The organic phase was dried over Na₂SO₄, filtered and the volatilesremoved under reduced pressure. The crude product was purified by flashcolumn chromatography, elution gradient 0 to 5% EtOAc in petroleumether. Pure produce containing fractions were evaporated to dryness toafford ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate(Intermediate 24; 123 g, 67.4%) as a solid. ¹H NMR (400 MHz, CDCl₃, 23°C.) δ 0.02 (9H, s), 0.93-1.03 (2H, m), 1.48 (3H, t), 2.71-2.76 (3H, m),3.59-3.69 (2H, m), 4.48 (2H, q), 5.85 (2H, s), 8.16 (1H, s), 8.42-8.47(1H, m). m/z (ES+), [M+H]+=397.

Intermediate 25 Ethyl4-(2,5-dichloropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate

2nd Generation XPhos precatalyst (0.788 g, 1.00 mmol) was added to ethyl4-bromo-1-((2-(trimethyl silyl)ethoxy)methyl)-1H-imidazole-2-carboxylate(Intermediate 25a, also commercially available; 7 g, 20.04 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (7.63 g,30.06 mmol) and KOAc (3.93 g, 40.08 mmol) in 1,4-dioxane (100 mL) at 25°C. under nitrogen. The resulting mixture was then stirred at 85° C. for3 hours. The reaction mixture was filtered and the filtrate was used inthe next step directly without further purification. m/z (ES+),[M+H]+=315.

Alternative Method to Prepare Intermediate 25:

2-Dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (12.28 g,25.77 mmol) was added totris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (11.11 g,10.74 mmol) in 1,4-dioxane (2000 mL) at room temperature under nitrogen.The resulting mixture was stirred then stirred at room temperature for45 hours. Ethyl4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate(150 g, 429.43 mmol), bis(pinacolato)diboron (131 g, 515.32 mmol) andpotassium acetate (126 g, 1288.29 mmol) were added at room temperatureunder nitrogen. The resulting mixture was stirred at 80° C. for 8 hours.The reaction mixture was then filtered through celite. The solvent wasremoved under reduced pressure to afford(2-(ethoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)boronicacid (Intermediate 25; 135 g, 100%) as a yellow oil. m/z (ES+),[M+H]+=315.

Intermediate 25a Ethyl4-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate

NBS (158 g, 887.56 mmol) was added portionwise to ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (Intermediate 25b; 160g, 591.71 mmol) in DMF (1200 mL) and DCM (1300 mL) at 0° C. Theresulting reaction was stirred at 25° C. for 48 hours. The the volatileswere removed under reduced pressure and EtOAc (7 L) was added. Theorganic phase was then washed sequentially with saturated NaHCO₃ (1 L),water (1 L), and saturated brine (750 mL). The organic layer was driedover Na₂SO₄, filtered and evaporated to afford the crude product whichwas purified by flash silica chromatography, elution gradient 0 to 4%EtOAc in petroleum ether. Pure fractions were evaporated to dryness toafford ethyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (Intermediate 25a; 106g, 51.3%) as a pale yellow oil which solidified on standing. ¹H NMR (300MHz, DMSO) δ −0.07 (9H, s), 0.77-0.85 (2H, m), 1.29 (3H, t), 3.53 (2H,t), 4.30 (2H, q), 5.66 (2H, s), 7.83 (1H, s). m/z (ES+), [M+H]+=349/351.

Intermediate 25b Ethyl1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate

SEM-Cl (286 g, 1712.55 mmol) was added dropwise to ethyl1H-imidazole-2-carboxylate (200 g, 1427.12 mmol) and K₂CO₃ (592 g,4281.37 mmol) in acetone (3 L) at 0° C. The resulting mixture wasstirred at ambient temperature for 16 hours. The resulting precipitatewas removed by filtration and washed with EtOAc (1 L). The combinedorganic layers were then dried over Na₂SO₄ and the volatiles removedunder reduced pressure. The result crude material was purified by flashsilica chromatography, elution gradient 0 to 30% EtOAc in petroleumether. Pure fractions were evaporated to dryness to afford ethyl1-((2-(trimethyl silyl)ethoxy)methyl)-1H-imidazole-2-carboxylate(Intermediate 25b; 328 g, 85%) as a pale yellow oil. ¹H NMR (300 MHz,CDCl₃) δ −0.01 (9H, s), 090-0.97 (2H, m), 1.45 (3H, t), 3.50-3.63 (2H,m), 4.43 (2H, q), 5.81 (2H, s), 7.22 (1H, s), 7.28 (1H, s). m/z (ES+),[M+H]+=271.

Example 6(S)-2-(5-Chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

2nd Generation XantPhos precatalyst (20.95 mg, 0.02 mmol) was added to(S)-2-(2,5-dichloropyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 26; 100 mg, 0.24 mmol), 1-methyl-1H-pyrazol-5-amine(Intermediate 26; 57.2 mg, 0.59 mmol) and Cs₂CO₃ (154 mg, 0.47 mmol) in1,4-dioxane (5 mL) at 25° C. under nitrogen and the resulting mixturewas stirred at 100° C. for 8 hours. The volatiles were removed underreduced pressure and the crude product was purified by flash silicachromatography, elution gradient 0 to 6% MeOH in DCM. Pure fractionswere evaporated to dryness to afford a yellow residue. The product wasfurther purified by preparative HPLC (XSelect CSH Prep C18 OBD column,5μ silica, 19 mm diameter, 150 mm length), using decreasingly polarmixtures of water (containing 0.03% NH₃) and MeCN as eluents. Fractionscontaining the desired compound were evaporated to dryness to afford(S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 6; 16.00 mg, 14%) as a white solid. ¹H NMR (400 MHz, DMSO, 22°C.) δ 1.15 (3H, d), 3.71 (3H, s), 4.00 (1H, s), 4.34 (2H, d), 4.47 (1H,dd), 5.07 (1H, d), 6.32 (1H, s), 7.27 (1H, s), 7.35 (1H, d), 7.38-7.51(2H, m), 8.19 (1H, s), 8.54 (1H, s), 9.73 (1H, s). m/z (ES+),[M+H]+=485.

Intermediate 26(S)-2-(2,5-Dichloropyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

A solution of (S)-ethyl4-(2,5-dichloropyrimidin-4-yl)-1-(2-((3,4-difluorobenzyl)amino)propyl)-1H-imidazole-2-carboxylate(Intermediate 27; 200 mg, 0.43 mmol) in NH₃ (7N in MeOH, 5 mL, 35.00mmol) was stirred at 50° C. for 2 hours. The solvent was then removedunder reduced pressure. The crude product was then purified by flashsilica chromatography, elution gradient 0 to 5% MeOH in DCM. Purefractions were evaporated to dryness to afford(S)-2-(2,5-dichloropyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 26; 100 mg, 55.4%) as a yellow solid. m/z (ES+),[M+H]+=424.

Intermediate 27 (S)-Ethyl4-(2,5-dichloropyrimidin-4-yl)-1-(2-((3,4-difluorobenzyl)amino)propyl)-1H-imidazole-2-carboxylate

3,4-Difluorobenzaldehyde (74.9 mg, 0.53 mmol) was added to (S)-ethyl1-(2-aminopropyl)-4-(2,5-dichloropyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 28; 200 mg, 0.48 mmol) in DCM (10 mL) at25° C. under nitrogen. After stirring at 40° C. for 3 hours, sodiumtriacetoxyborohydride (305 mg, 1.44 mmol) was added and the resultingmixture was stirred at 25° C. for 3 hours. The reaction mixture was thenquenched with saturated NaHCO₃ (20 mL), extracted with DCM (2×50 mL),the organic layer was dried over Na₂SO₄, filtered and evaporated toafford the crude product (S)-ethyl4-(2,5-dichloropyrimidin-4-yl)-1-(2-((3,4-difluorobenzyl)amino)propyl)-1H-imidazole-2-carboxylate(Intermediate 27; 200 mg, 89%) as a yellow solid. The product was usedin the next step directly without further purification. m/z (ES+),[M+H]+=470.

Intermediate 28 (S)-Ethyl1-(2-aminopropyl)-4-(2,5-dichloropyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride

A solution of (S)-ethyl1-(2-((tert-butoxycarbonyl)amino)propyl)-4-(2,5-dichloropyrimidin-4-yl)-1H-imidazole-2-carboxylate(Intermediate 29; 2.8 g, 6.30 mmol) in HCl (4N in 1,4-dioxane, 20 mL)was stirred at 25° C. overnight. The precipitate was collected byfiltration, washed with EtOAc (20 mL) and dried under vacuum to afford(S)-ethyl 1-(2-aminopropyl)-4-(2,5-dichloropyrimidin-4-yl)-1H-imidazole-2-carboxylate (Intermediate 28;2.50 g, 95%) as a white solid. ¹H NMR (400 MHz, DMSO, 24° C.) δ 1.26(3H, d), 1.37 (3H, t), 3.75 (1H, s), 4.40 (2H, d), 4.63 (2H, d), 8.05(3H, s), 8.61 (1H, s), 8.94 (1H, s). m/z (ES+), [M+H]+=344.

Intermediate 29 (S)-Ethyl1-(2-((tert-butoxycarbonyl)amino)propyl)-4-(2,5-dichloropyrimidin-4-yl)-1H-imidazole-2-carboxylate

1M HCl (20 mL, 20.00 mmol) was added to(S)-(tert-butoxycarbonyl)(1-(4-(2,5-dichloropyrimidin-4-yl)-2-(ethoxycarbonyl)-1H-imidazol-1-yl)propan-2-yl)sulfamicacid (Intermediate 30; 6 g, 11.44 mmol) in EtOH (20 mL) at 25° C. underair. The resulting mixture was stirred at 50° C. for 20 minutes. Thereaction mixture was quenched with saturated NaHCO₃ (50 mL), extractedwith DCM (3×100 mL), the organic layer was dried over Na₂SO₄, filteredand evaporated to afford yellow residue. The crude product was purifiedby flash silica chromatography, elution gradient 0 to 30% EtOAc inpetroleum ether. Pure fractions were evaporated to dryness to afford(S)-ethyl 1-(2-((tert-butoxycarbonyl)amino)propyl)-4-(2,5-dichloropyrimidin-4-yl)-1H-imidazole-2-carboxylate (Intermediate 29;2.80 g, 55.1%) as a white solid. ¹H NMR (300 MHz, CDCl₃, 27° C.) δ 1.24(3H, d), 1.35 (9H, s), 1.46 (2H, t), 4.03-4.17 (1H, m), 4.46 (2H, q),4.58-4.69 (2H, m), 5.30 (1H, s), 8.08 (1H, s), 8.58 (1H, s). m/z (ES+),[M+H]+=444.

Intermediate 30(S)-(tert-Butoxycarbonyl)(1-(4-(2,5-dichloropyrimidin-4-yl)-2-(ethoxycarbonyl)-1H-imidazol-1-yl)propan-2-yl)sulfamicacid

(S)-tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(Intermediate 12; 4.59 g, 19.33 mmol) was added portionwise to ethyl4-(2,5-dichloropyrimidin-4-yl)-1H-imidazole-2-carboxylate (Intermediate31; 3.7 g, 12.89 mmol) and K₂CO₃ (5.34 g, 38.66 mmol) in acetonitrile(30 mL) at 80° C. under nitrogen. The resulting mixture was stirred at85° C. for 12 hours. The reaction mixture was then filtered and washedwith MeCN. The solvent was removed under reduced pressure to afford thedesired product(S)-(tert-butoxycarbonyl)(1-(4-(2,5-dichloropyrimidin-4-yl)-2-(ethoxycarbonyl)-1H-imidazol-1-yl)propan-2-yl)sulfamicacid (Intermediate 30; 6.00 g, 89%) as a yellow oil. The product wasused in the next step directly without further purification. m/z (ES+),[M+H]+=524.

Intermediate 31 Ethyl4-(2,5-dichloropyrimidin-4-yl)-1H-imidazole-2-carboxylate

Trifluoroacetic acid (20 mL, 259.60 mmol) was added to ethyl4-(2,5-dichloropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (Intermediate 32; 5.6 g,13.42 mmol) in DCM (20 mL) at 25° C. The resulting mixture was stirredat 25° C. for 12 hours. The solvent was removed under reduced pressureand the reaction mixture was basified with excess saturated NaHCO₃. Theresulting precipitate formed was collected by filtration, washed withwater (100 mL) and dried under vacuum to afford ethyl4-(2,5-dichloropyrimidin-4-yl)-1H-imidazole-2-carboxylate (Intermediate31; 3.70 g, 96%) as a white solid. ¹H NMR (400 MHz, DMSO, 25° C.) δ 1.36(3H, t), 4.39 (2H, q), 7.59 (1H, s), 8.32 (1H, s), 8.90 (1H, s). m/z(ES+), [M+H]+=287.

Intermediate 32 Ethyl4-(2,5-dichloropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate

Pd(Ph₃P)₄ (1.14 g, 0.99 mmol) was added to(2-(ethoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)boronic acid (Intermediate 25; 6.2g, 19.73 mmol), 2,4,5-trichloropyrimidine (3.62 g, 19.73 mmol) andCs₂CO₃ (9.64 g, 29.60 mmol) in 1,4-dioxane (160 mL) and water (40 mL) at25° C. under nitrogen. The resulting mixture was stirred at 85° C. for 2hours. The reaction mixture was poured into water (150 mL), extractedwith DCM (2×250 mL), the organic layers were dried over Na₂SO₄, filteredand evaporated to afford a yellow residue. The crude product waspurified by flash silica chromatography, elution gradient 0 to 10% EtOAcin petroleum ether. Pure fractions were evaporated to dryness to affordethyl 4-(2,5-dichloropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (Intermediate 32; 5.60g, 68%) as a white solid. ¹H NMR (400 MHz, CDCl₃, 25° C.) δ 0.01 (9H,s), 0.93-1.02 (2H, m), 1.48 (3H, t), 3.60-3.69 (2H, m), 4.48 (2H, q),5.89 (2H, s), 8.29 (1H, s), 8.63 (1H, s). m/z (ES+), [M+H]+=417.

Example 7(S)-2-(5-Chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-(3-methoxybenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

2nd Generation XantPhos precatalyst (31.9 mg, 0.04 mmol) was added to(S)-2-(2,5-dichloropyrimidin-4-yl)-7-(3-methoxybenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 33; 150 mg, 0.36 mmol), 1-methyl-1H-pyrazol-5-amine (87mg, 0.90 mmol) and Cs₂CO₃ (234 mg, 0.72 mmol) in 1,4-dioxane (5 mL) at25° C. under nitrogen. The resulting mixture was stirred at 100° C. for8 hours. The solvent was then removed under reduced pressure and thecrude product was purified by flash silica chromatography, elutiongradient 0 to 6% MeOH in DCM. Pure fractions were evaporated to drynessto afford a yellow residue. The residue was further purified bypreparative HPLC (XSelect CSH Prep C18 OBD column, 5 silica, 19 mmdiameter, 150 mm length), using decreasingly polar mixtures of water(containing 0.03% NH₃) and MeCN as eluents.

Fractions containing the desired compound were evaporated to dryness toafford(S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-(3-methoxybenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 7; 31.0 mg, 18.05%) as a white solid. ¹H NMR (400 MHz, DMSO,20° C.) δ 1.13 (3H, d), 3.71 (3H, s), 3.76 (3H, s), 3.96 (1H, d),4.26-4.36 (2H, m), 4.41 (1H, dd), 5.09 (1H, d), 6.32 (1H, s), 6.84-6.91(1H, m), 6.96 (2H, d), 7.24-7.38 (2H, m), 8.20 (1H, s), 8.54 (1H, s),9.74 (1H, s). m/z (ES+), [M+H]+=479.

Intermediate 33(S)-2-(2,5-Dichloropyrimidin-4-yl)-7-(3-methoxybenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

TEA (0.162 mL, 1.16 mmol) was added to (S)-ethyl4-(2,5-dichloropyrimidin-4-yl)-1-(2-((3-methoxybenzyl)amino)propyl)-1H-imidazole-2-carboxylate(Intermediate 34; 180 mg, 0.39 mmol) in toluene (8 mL) at 25° C. underair. The resulting mixture was stirred at 140° C. for 8 hours. Thesolvent was then removed under reduced pressure and the crude productwas purified by flash silica chromatography, elution gradient 0 to 3%MeOH in DCM. Pure fractions were evaporated to dryness to afford(S)-2-(2,5-dichloropyrimidin-4-yl)-7-(3-methoxybenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 33; 150 mg, 93%) as a yellow solid. m/z (ES+),[M+Na]+=418.(S)-2-(2,5-dichloropyrimidin-4-yl)-7-(3-methoxybenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 33) was used in the next step without furtherpurification.

Intermediate 34 (S)-Ethyl4-(2,5-dichloropyrimidin-4-yl)-1-(2-((3-methoxybenzyl)amino)propyl)-1H-imidazole-2-carboxylate

3-methoxybenzaldehyde (71.8 mg, 0.53 mmol) was added to (S)-ethyl1-(2-aminopropyl)-4-(2,5-dichloropyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 28; 200 mg, 0.48 mmol) in DCM (10 mL) at25° C. under nitrogen. After stirring at 40° C. for 3 hours, sodiumtriacetoxyborohydride (305 mg, 1.44 mmol) was added and the resultingmixture was stirred at 25° C. for 3 hours. The reaction mixture wasquenched with saturated NaHCO₃ (20 mL), extracted with DCM (2×50 mL),the organic layers were dried over Na₂SO₄, filtered and evaporated toafford a yellow residue. The crude product was purified by flash silicachromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractionswere evaporated to dryness to afford (S)-ethyl4-(2,5-dichloropyrimidin-4-yl)-1-(2-((3-methoxybenzyl)amino)propyl)-1H-imidazole-2-carboxylate(Intermediate 34; 180 mg, 81%) as a yellow solid. m/z (ES+), [M+H]+=464.

Example 8(S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6-methyl-7-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

2nd Generation XantPhos precatalyst (12.41 mg, 0.01 mmol) was added to(S)-2-(2,5-dichloropyrimidin-4-yl)-6-methyl-7-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 35; 64 mg, 0.14 mmol), 1-methyl-1H-pyrazol-5-amine (33.9mg, 0.35 mmol) and Cs₂CO₃ (91 mg, 0.28 mmol) in 1,4-dioxane (5 mL) at25° C. under nitrogen and the resulting mixture was stirred at 100° C.for 8 hours. The solvent was then removed under reduced pressure. Thecrude product was purified by flash silica chromatography, elutiongradient 0 to 6% MeOH in DCM. Pure fractions were evaporated to drynessto afford a yellow residue. This residue was further purified bypreparative HPLC (XSelect CSH Prep C18 OBD column, 5μ silica, 19 mmdiameter, 150 mm length), using decreasingly polar mixtures of water(containing 0.03% NH₃) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford(S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6-methyl-7-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 8; 15.2 mg, 21%) as a white solid. ¹H NMR (400 MHz, DMSO, 20.1°C.) δ 1.25 (3H, d), 3.71 (3H, s), 4.18 (1H, ddd), 4.42 (1H, dd),4.60-4.69 (2H, m), 5.23 (1H, d), 6.32 (1H, d), 7.35 (1H, d), 7.94 (1H,d), 8.25 (1H, s), 8.55 (1H, s), 9.03 (1H, d), 9.74 (1H, s). m/z (ES+),[M+H]+=519.

Intermediate 35(S)-2-(2,5-dichloropyrimidin-4-yl)-6-methyl-7-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

TEA (0.129 mL, 0.93 mmol) was added to (S)-ethyl4-(2,5-dichloropyrimidin-4-yl)-1-(2-(((2-(trifluoromethyl)pyrimidin-4-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate(Intermediate 36; 156 mg, 0.31 mmol) in toluene (3 mL) at 25° C. underair. The resulting mixture was stirred at 140° C. for 4 hours. Thesolvent was then removed under reduced pressure. The crude product waspurified by flash silica chromatography, elution gradient 3 to 4% MeOHin DCM. Pure fractions were evaporated to dryness to afford(S)-2-(2,5-dichloropyrimidin-4-yl)-6-methyl-7-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 35; 64.0 mg, 45.2%) as a yellow solid. m/z (ES+),[M+H]+=458.

Intermediate 36 (S)-Ethyl4-(2,5-dichloropyrimidin-4-yl)-1-(2-(((2-(trifluoromethyl)pyrimidin-4-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate

2-(Trifluoromethyl)pyrimidine-4-carbaldehyde (127 mg, 0.72 mmol) wasadded to (S)-ethyl 1-(2-aminopropyl)-4-(2,5-dichloropyrimidin-4-yl)-1H-imidazole-2-carboxylate dihydrochloride(Intermediate 28; 300 mg, 0.72 mmol) in DCM (10 mL) at 25° C. under air.The resulting solution was stirred at 40° C. for 3 hours. Sodiumtriacetoxyborohydride (457 mg, 2.16 mmol) was added to reaction mixtureat 25° C. The resulting solution was stirred at 25° C. for 12 hours. Thereaction mixture was quenched with water (10 mL) and extracted with DCM(3×15 mL). The organic layers were combined and washed with brine (15mL), dried over Na₂SO₄, filtered and evaporated to afford yellow oil.The crude product was purified by flash silica chromatography, elutiongradient 2 to 3% MeOH in DCM. Pure fractions were evaporated to drynessto afford (S)-ethyl4-(2,5-dichloropyrimidin-4-yl)-1-(2-(((2-(trifluoromethyl)pyrimidin-4-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate(Intermediate 36; 156 mg, 43%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃,20.2° C.) δ 1.26-1.38 (3H, m), 1.44 (3H, t), 2.85 (1H, s), 4.01 (2H, q),4.33-4.51 (2H, m), 4.55-4.70 (1H, m), 4.92 (2H, s), 7.65 (1H, d), 8.65(1H, d), 8.74-8.85 (1H, m), 8.91 (1H, d). m/z (ES+), [M+H]+=504.

Example 9(S)-2-(5-Chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

2nd Generation XantPhos precatalyst (24.28 mg, 0.03 mmol) was added to(S)-2-(2,5-dichloropyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 37; 120 mg, 0.27 mmol), 1-methyl-1H-pyrazol-5-amine (66.3mg, 0.68 mmol) and Cs₂CO₃ (178 mg, 0.55 mmol) in 1,4-dioxane (5 mL) at25° C. under nitrogen. The resulting mixture was stirred at 100° C. for8 hours. The solvent was then removed under reduced pressure and thecrude product was purified by flash silica chromatography, elutiongradient 0 to 6% MeOH in DCM. Pure fractions were evaporated to drynessto afford a yellow residue. This residue was further purified bypreparative HPLC (XSelect CSH Prep C18 OBD column, 5 silica, 19 mmdiameter, 150 mm length), using decreasingly polar mixtures of water(containing 0.03% NH₃) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford(S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 9; 27 mg, 19.8%) as a white solid. ¹H NMR (400 MHz, DMSO, 23°C.) δ 1.21 (3H, d), 3.71 (3H, s), 4.12 (1H, s), 4.38 (1H, d), 4.48-4.63(2H, m), 5.22 (1H, d), 6.32 (1H, s), 6.97 (1H, t), 7.35 (1H, d),7.59-7.67 (2H, m), 8.00 (1H, t), 8.23 (1H, s), 8.54 (1H, s), 9.72 (1H,s). m/z (ES+), [M+H]+=500.

Intermediate 37(S)-2-(2,5-Dichloropyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

A solution of (S)-ethyl4-(2,5-dichloropyrimidin-4-yl)-1-(2-(((6-(difluoromethyl)pyridin-2-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate(Intermediate 38; 200 mg, 0.41 mmol) in NH₃ (7N in MeOH, 5 mL, 35.00mmol) was stirred at 50° C. for 2 hours. The solvent was then removedunder reduced pressure and the crude product was purified by flashsilica chromatography, elution gradient 0 to 5% MeOH in DCM. Purefractions were evaporated to dryness to afford(S)-2-(2,5-dichloropyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 37; 120 mg, 66.3%) as a yellow solid. m/z (ES+),[M+H]+=439.

Intermediate 38 (S)-Ethyl4-(2,5-dichloropyrimidin-4-yl)-1-(2-(((6-(difluoromethyl)pyridin-2-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate

6-(difluoromethyl)picolinaldehyde (Intermediate 39; 226 mg, 1.44 mmol)was added to (S)-ethyl1-(2-aminopropyl)-4-(2,5-dichloropyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 28; 200 mg, 0.48 mmol) in DCM (15 mL) at25° C. under nitrogen. After stirring at 40° C. for 3 hours, sodiumtriacetoxyborohydride (305 mg, 1.44 mmol) was added and the resultingmixture was stirred at 25° C. for 3 hours. The reaction mixture wasquenched with saturated NaHCO₃ (20 mL) and extracted with DCM (2×50 mL).The combined organic layers was dried over Na₂SO₄, filtered andevaporated to afford the desired product (S)-ethyl4-(2,5-dichloropyrimidin-4-yl)-1-(2-(((6-(difluoromethyl)pyridin-2-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate(Intermediate 38; 200 mg, 86%) as a yellow solid. m/z (ES+), [M+H]+=485.

Intermediate 39 6-(Difluoromethyl)picolinaldehyde

LiAlH₄ (1.141 g, 30.07 mmol) was added to6-(difluoromethyl)-N-methoxy-N-methylpicolinamide (Intermediate 40; 5 g,23.13 mmol) in THF (80 mL) cooled to −78° C. under nitrogen and theresulting solution was stirred at −78° C. for 1 hour. The reaction wasdiluted EtOAc (6 mL), then quenched with water (1 mL) at −78° C. NaOH(15% aqueous, 3.0 mL) and water (1.0 mL) were added and the resultingsolids were filtered off. The filtrate was dried over Na₂SO₄, filteredand evaporated to afford 6-(difluoromethyl)picolinaldehyde (Intermediate39; 3.60 g, 99%) as a yellow oil. The product was used in the next stepwithout further purification. m/z (ES+), [M+H]+=158.

Intermediate 40 6-(Difluoromethyl)-N-methoxy-N-methylpicolinamide

Oxalyl dichloride (7.92 g, 62.39 mmol) was added dropwise to6-(difluoromethyl)picolinic acid (Intermediate 41; 5.4 g, 31.19 mmol)and DMF (0.242 mL, 3.12 mmol) in DCM (30 mL) at 25° C. under nitrogen.The resulting mixture was stirred at 25° C. for 2 hours. The solvent wasthen removed under reduced pressure to afford the desired product6-(difluoromethyl)picolinoyl chloride (6.00 g, 100%) as a yellow oilwhich was used immediately. N,O-dimethylhydroxylamine hydrochloride(4.58 g, 46.98 mmol) was added portionwise to6-(difluoromethyl)picolinoyl chloride (6.0 g, 31.32 mmol) and TEA (17.46mL, 125.29 mmol) in DCM (50 mL) at 25° C. under nitrogen. The resultingmixture was then stirred at 25° C. for 12 hours. The reaction mixturewas quenched with water (50 mL), extracted with DCM (2×100 mL), theorganic layers were dried over Na₂SO₄, filtered and evaporated to affordyellow residue. The crude product was purified by flash silicachromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Purefractions were evaporated to dryness to afford6-(difluoromethyl)-N-methoxy-N-methylpicolinamide (Intermediate 40; 5.00g, 73.8%) as a yellow liquid. ¹H NMR (400 MHz, CDCl₃, 20° C.) δ 3.42(3H, s), 3.80 (3H, s), 6.68 (1H, t), 7.74 (2H, d), 7.98 (1H, t). m/z(ES+), [M+H]+=217.

Intermediate 41 6-(Difluoromethyl)picolinic acid

A solution of methyl 6-(difluoromethyl)picolinate (Intermediate 42; 6.2g, 33.13 mmol) in HCl (30 mL, 360.00 mmol) was heated at 90° C. for 8hours. The solvent was removed under reduced pressure to afford thedesired product 6-(difluoromethyl)picolinic acid (Intermediate 41; 5.40g, 94%) as a white solid. ¹H NMR (400 MHz, DMSO, 20° C.) δ 7.05 (1H, t),7.94 (1H, t), 8.16-8.22 (2H, m), 13.56 (1H, s). m/z (ES+), [M+H]+=174.

Intermediate 42 Methyl 6-(difluoromethyl)picolinate

2-bromo-6-(difluoromethyl)pyridine (Intermediate 43; 8.5 g, 40.86 mmol),potassium acetate (8.02 g, 81.73 mmol) and Pd(dppf)Cl₂ (1.495 g, 2.04mmol) in MeOH (100 mL) were stirred under an atmosphere of CO at 10 atmat 70° C. for 6 hours. The reaction mixture was then filtered and thefiltrate was evaporated under reduced pressure. The crude product waspurified by flash silica chromatography, elution gradient 0 to 20% EtOAcin petroleum ether. Pure fractions were evaporated to dryness to affordmethyl 6-(difluoromethyl)picolinate (Intermediate 42; 6.20 g, 81%) as acolourless liquid. ¹H NMR (400 MHz, CDCl₃, 20° C.) δ 4.06 (3H, s), 6.79(1H, t), 7.89 (1H, d), 8.05 (1H, t), 8.24-8.31 (1H, m). m/z (ES+),[M+H]+=188.

Intermediate 43 2-Bromo-6-(difluoromethyl)pyridine

DAST (17.76 mL, 134.40 mmol) was added dropwise to6-bromopicolinaldehyde (10 g, 53.76 mmol) in DCM (150 mL) cooled to 0°C. over a period of 10 minutes. The resulting mixture was stirred at 25°C. for 12 hours. The reaction mixture was quenched with water (20 mL)and basified by the addition of NaHCO₃ (sat. aq.). The aqueous phase wasextracted with DCM (3×150 mL), the organic layer was dried over Na₂SO₄,filtered and evaporated to afford a brown liquid. The crude product waspurified by flash silica chromatography, elution gradient 0 to 8% EtOAcin petroleum ether. Pure fractions were evaporated to dryness to afford2-bromo-6-(difluoromethyl)pyridine (Intermediate 43; 9.00 g, 80%) as acolourless liquid. ¹H NMR (400 MHz, CDCl₃, 22° C.) δ 6.59 (1H, t),7.58-7.65 (2H, m), 7.71 (1H, t). m/z (ES+), [M+H]+=208/210.

Example 10(S)-2-(5-Chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6-methyl-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

2nd Generation XantPhos precatalyst (14.97 mg, 0.02 mmol) was added to(S)-2-(2,5-dichloropyrimidin-4-yl)-6-methyl-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 44; 77 mg, 0.17 mmol), 1-methyl-1H-pyrazol-5-amine (40.9mg, 0.42 mmol) and Cs₂CO₃ (110 mg, 0.34 mmol) in 1,4-dioxane (3 mL) at25° C. under nitrogen. The resulting mixture was stirred at 100° C. for6 hours. The solvent was removed under reduced pressure and the crudeproduct was purified by flash silica chromatography, elution gradient 5to 6% MeOH in DCM. Pure fractions were evaporated to dryness to afford ayellow crude product. This crude product was further purified bypreparative HPLC (XSelect CSH Prep C18 OBD column, 5 silica, 19 mmdiameter, 150 mm length), using decreasingly polar mixtures of water(containing 0.03% NH₃) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford(S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6-methyl-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 10; 18.5 mg, 21%) as a white solid. ¹H NMR (400 MHz, DMSO,23.0° C.) δ 1.22 (3H, d), 3.71 (3H, s), 4.15 (1H, ddd), 4.40 (1H, dd),4.53-4.64 (2H, m), 5.23 (1H, d), 6.32 (1H, d), 7.35 (1H, d), 7.75-7.87(2H, m), 8.10 (1H, t), 8.23 (1H, s), 8.54 (1H, s), 9.73 (1H, s). m/z(ES+), [M+H]+=518.

Intermediate 44(S)-2-(2,5-Dichloropyrimidin-4-yl)-6-methyl-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

NH₃ (7N in MeOH, 3 mL) was added to (S)-ethyl4-(2,5-dichloropyrimidin-4-yl)-1-(2-(((6-(trifluoromethyl)pyridin-2-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate(Intermediate 45; 98 mg, 0.19 mmol). The resulting solution was stirredat 50° C. for 2 hours. The solvent was removed by distillation undervacuum to afford(S)-2-(2,5-dichloropyrimidin-4-yl)-6-methyl-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 44; 77 mg, 86%) as a colourless oil. The product was usedin the next step directly without further purification. m/z (ES+),[M+H]+=457.

Intermediate 45 (S)-Ethyl4-(2,5-dichloropyrimidin-4-yl)-1-(2-(((6-(trifluoromethyl)pyridin-2-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate

6-(trifluoromethyl)picolinaldehyde (115 mg, 0.66 mmol) was added to(S)-ethyl1-(2-aminopropyl)-4-(2,5-dichloropyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 28; 250 mg, 0.60 mmol) in DCM (10 mL) at20° C. under nitrogen. The resulting solution was stirred at 40° C. for4 hours. Sodium triacetoxyborohydride (254 mg, 1.20 mmol) was then addedat 20° C. and the resulting solution was stirred at 20° C. for 12 hours.The reaction mixture was quenched with water (10 mL), extracted with DCM(3×15 mL). The combined organic layers were washed with brine (15 mL),dried over Na₂SO₄, filtered and evaporated to afford a yellow oil. Thecrude product was purified by flash silica chromatography, elutiongradient 2 to 2.5% MeOH in DCM. Pure fractions were evaporated todryness to afford (S)-ethyl4-(2,5-dichloropyrimidin-4-yl)-1-(2-(((6-(trifluoromethyl)pyridin-2-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate(Intermediate 45; 98 mg, 32.5%) as a yellow oil. m/z (ES+), [M+H]+=503.

Example 11(S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6-methyl-7-((6-methylpyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

2nd Generation XantPhos precatalyst (26.4 mg, 0.03 mmol) was added to(S)-2-(2,5-dichloropyrimidin-4-yl)-6-methyl-7-((6-methylpyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 46; 120 mg, 0.30 mmol), 1-methyl-1H-pyrazol-5-amine (72.2mg, 0.74 mmol) and Cs₂CO₃ (194 mg, 0.60 mmol) in 1,4-dioxane (8 mL) at25° C. under nitrogen. The resulting mixture was stirred at 100° C. for8 hours. The solvent was then removed under reduced pressure. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 6% MeOH in DCM. Pure fractions were evaporated to dryness to afford ayellow residue. This residue was further purified by preparative HPLC(XSelect CSH Prep C18 OBD column, 5 silica, 19 mm diameter, 150 mmlength), using decreasingly polar mixtures of water (containing 0.03%NH₃) and MeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford(S)-2-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6-methyl-7-((6-methylpyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 11; 50 mg, 36.2%) as a white solid. ¹H NMR (400 MHz, DMSO, 22°C.) δ 1.19 (3H, d), 2.47 (3H, s), 3.70 (3H, s), 4.08 (1H, d), 4.32-4.43(2H, m), 4.53 (1H, dd), 5.15 (1H, d), 6.31 (1H, d), 7.21 (2H, dd), 7.34(1H, d), 7.68 (1H, t), 8.21 (1H, s), 8.53 (1H, s), 9.72 (1H, s). m/z(ES+), [M+H]+=464.

Intermediate 46(S)-2-(2,5-Dichloropyrimidin-4-yl)-6-methyl-7-((6-methylpyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

Sodium acetate (118 mg, 1.44 mmol) was added to (S)-ethyl1-(2-aminopropyl)-4-(2,5-dichloropyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 28; 200 mg, 0.48 mmol) and6-methylpicolinaldehyde (63.9 mg, 0.53 mmol) in MeOH (10 mL) at 20° C.under nitrogen. The resulting mixture was stirred at 25° C. for 30minutes. Sodium triacetoxyborohydride (203 mg, 0.96 mmol) was added andthe reaction mixture was stirred at 25° C. for 18 hours. The reactionwas quenched with saturated aqueous NaHCO₃ (25 mL) and the aqueous phasewas extracted with DCM (3×50 mL). The combined organic phases were driedover Na₂SO₄, filtered and evaporated to afford yellow residue. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford(S)-2-(2,5-dichloropyrimidin-4-yl)-6-methyl-7-((6-methylpyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 46; 120 mg, 62.1%) as a white solid. ¹H NMR (400 MHz,CDCl₃, 24° C.) δ 1.33 (3H, d), 2.60 (3H, s), 4.09 (1H, d), 4.19-4.46(2H, m), 4.52 (1H, d), 5.42 (1H, d), 7.15 (1H, s), 7.34 (1H, s), 7.63(1H, s), 8.02 (1H, s), 8.61 (1H, s). m/z (ES+), [M+H]+=403.

Example 127-(3-Chloro-4-fluorobenzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

2nd Generation XantPhos precatalyst (63.9 mg, 0.07 mmol) was added to7-(3-chloro-4-fluorobenzyl)-2-(2-chloro-5-methylpyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 47; 292 mg, 0.72 mmol), 1-methyl-1H-pyrazol-5-amine (140mg, 1.44 mmol) and Cs₂CO₃ (585 mg, 1.80 mmol) in 1,4-dioxane (3 mL) at25° C. under nitrogen. The resulting solution was stirred at 100° C. for4 hours. The solvent was removed by distillation under vacuum and thecrude product was purified by flash silica chromatography, elutiongradient 0 to 7% MeOH in DCM. Product containing fractions wereevaporated to dryness to afford crude product. This crude product waspurified further by preparative HPLC (XSelect CSH Prep C18 OBD column, 5silica, 19 mm diameter, 150 mm length), using decreasingly polarmixtures of water (containing 0.05% NH₄HCO₃) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness toafford7-(3-chloro-4-fluorobenzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 12; 59.7 mg, 17.79%) as a white solid. ¹H NMR (400 MHz, CDCl₃,20.1° C.) δ 2.70 (3H, s), 3.72 (2H, dd), 3.81 (3H, s), 4.26-4.34 (2H,m), 4.77 (2H, s), 6.31 (1H, d), 6.98 (1H, s), 7.15 (1H, t), 7.23-7.32(1H, m), 7.45 (1H, dd), 7.49 (1H, d), 7.73 (1H, s), 8.30 (1H, s). m/z(ES+), [M+H]+=467.

Intermediate 477-(3-Chloro-4-fluorobenzyl)-2-(2-chloro-5-methylpyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

NaH (68.3 mg, 1.71 mmol) was added to2-(2-chloro-5-methylpyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 48; 150 mg, 0.57 mmol) in DMF (5 mL) at 25° C. undernitrogen. The resulting solution was then stirred at 25° C. for 30minutes. 4-(bromomethyl)-2-chloro-1-fluorobenzene (254 mg, 1.14 mmol)was added at 25° C. and stirring continue for 2 hours. The reactionmixture was quenched with saturated aqueous NaHCO₃ (25 mL), theresulting precipitate was collected by filtration, washed with water (50mL) and dried under vacuum to afford7-(3-chloro-4-fluorobenzyl)-2-(2-chloro-5-methylpyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 48; 292 mg, >100%) as a yellow solid, which was usedwithout further purification. ¹H NMR (400 MHz, DMSO, 20.1° C.) δ 2.64(3H, s), 3.74-3.82 (2H, m), 4.35-4.43 (2H, m), 4.70 (2H, s), 7.34-7.49(2H, m), 7.60 (1H, ddd), 8.25 (1H, s), 8.61 (1H, s). m/z (ES+),[M+H]+=406.

Intermediate 48 2-(2-Chloro-5-methylpyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

NH₃ (7N in MeOH, 15 mL) was added to ethyl1-(2-aminoethyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 21; 1.3 g, 3.40 mmol) at 20° C. under airand the resulting solution was stirred at 20° C. for 12 hours. Thesolvent was removed by distillation under vacuum, the resulting solidwas slurried with water (50 mL), filtered and dried under vacuum toafford2-(2-chloro-5-methylpyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 48; 0.80 g, 89%) as a white solid, which was used withoutfurther purification. ¹H NMR (400 MHz, DMSO, 20.3° C.) δ 2.62 (3H, s),3.61 (2H, ddd), 4.29-4.37 (2H, m), 8.26 (1H, s), 8.35 (1H, t), 8.59 (1H,d). m/z (ES+), [M+H]+=264.

Example 137-(3-Chlorobenzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

2nd Generation XantPhos precatalyst (62.0 mg, 0.07 mmol) was added to2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3-chlorobenzyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 49; 271 mg, 0.70 mmol), 1-methyl-1H-pyrazol-5-amine (136mg, 1.40 mmol) and Cs₂CO₃ (569 mg, 1.75 mmol) in 1,4-dioxane (5 mL) at25° C. under nitrogen. The resulting solution was stirred at 100° C. for4 hours. The solvent was then removed by distillation under vacuum andthe crude product was purified by flash silica chromatography, elutiongradient 0 to 7% MeOH in DCM. Product containing fractions wereevaporated to dryness to afford crude product. This crude product wasfurther purified by preparative HPLC (XSelect CSH Prep C18 OBD column, 5silica, 19 mm diameter, 150 mm length), using decreasingly polarmixtures of water (containing 0.05% NH₄HCO₃) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness toafford7-(3-chlorobenzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 13; 43.5 mg, 13.9%) as a white solid. ¹H NMR (400 MHz, CDCl₃,20.1° C.) δ 2.69 (3H, s), 3.68-3.76 (2H, m), 3.81 (3H, s), 4.29 (2H,dd), 4.80 (2H, s), 6.31 (1H, d), 7.06 (1H, s), 7.25-7.29 (1H, m),7.30-7.34 (2H, m), 7.36-7.39 (1H, m), 7.49 (1H, d), 7.73 (1H, s), 8.29(1H, s). m/z (ES+), [M+H]+=449.

Intermediate 492-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3-chlorobenzyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

NaH (68.3 mg, 1.71 mmol) was added to2-(2-chloro-5-methylpyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 48; 150 mg, 0.57 mmol) in DMF (5 mL) at 25° C. undernitrogen. The resulting solution was stirred at 25° C. for 30 minutes.1-(bromomethyl)-3-chlorobenzene (234 mg, 1.14 mmol) was added and theresulting solution was stirred at 25° C. for 2 hours. The reactionmixture was quenched with saturated NaHCO₃ (25 mL), the resultingprecipitate was collected by filtration, washed with water (50 mL) anddried under vacuum to afford2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3-chlorobenzyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 49; 271 mg) as a yellow solid, which was used withoutfurther purification. ¹H NMR (400 MHz, CDCl₃, 20.1° C.) δ 2.64 (3H, s),3.74-3.82 (2H, m), 4.36-4.44 (2H, m), 4.72 (2H, s), 7.39-7.48 (4H, m),8.26 (1H, s), 8.61 (1H, s). m/z (ES+) [M+H]+=388.

Example 147-(3-(Difluoromethyl)benzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

2nd Generation XantPhos precatalyst (61.6 mg, 0.07 mmol) was added to2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3-(difluoromethyl)benzyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 50; 280 mg, 0.69 mmol), 1-methyl-1H-pyrazol-5-amine (135mg, 1.39 mmol) and Cs₂CO₃ (565 mg, 1.73 mmol) in 1,4-dioxane (5 mL) at25° C. under nitrogen. The resulting solution was stirred at 100° C. for4 hours. The solvent was then removed by distillation under vacuum. Thecrude product was purified by flash silica chromatography, elutiongradient 0 to 7% MeOH in DCM. Compound containing fractions wereevaporated to dryness to afford impure product. This impure product waspurified further by preparative HPLC (XSelect CSH Prep C18 OBD column, 5silica, 19 mm diameter, 150 mm length), using decreasingly polarmixtures of water (containing 0.05% NH₄HCO₃) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness toafford7-(3-(difluoromethyl)benzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 14; 14; 69.6 mg, 21.6%) as a white solid. ¹H NMR (400 MHz,CDCl₃, 20.2° C.) δ 2.70 (3H, s), 3.68-3.76 (2H, m), 3.81 (3H, s),4.24-4.32 (2H, m), 4.88 (2H, s), 6.31 (1H, d), 6.66 (1H, t), 6.98 (1H,s), 7.43-7.56 (5H, m), 7.73 (1H, s), 8.30 (1H, s). m/z (ES+),[M+H]+=465.

Intermediate 502-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3-(difluoromethyl)benzyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

NaH (68.3 mg, 1.71 mmol) was added to2-(2-chloro-5-methylpyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(150 mg, 0.57 mmol) in DMF (5 mL) at 25° C. under nitrogen and theresulting solution was stirred at 25° C. for 30 minutes.1-(bromomethyl)-3-(difluoromethyl)benzene (251 mg, 1.14 mmol) was addedand the resulting solution was stirred at 25° C. for 2 hours. Thereaction mixture was quenched with saturated NaHCO₃ (25 mL) and theresulting precipitate was collected by filtration, washed with water (50mL) and dried under vacuum to afford2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3-(difluoromethyl)benzyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 50; 280 mg) as a yellow solid, which was used withoutfurther purification. ¹H NMR (400 MHz, DMSO, 19.9° C.) δ 2.64 (3H, s),3.74-3.82 (2H, m), 4.36-4.44 (2H, m), 4.79 (2H, s), 7.06 (1H, td),7.49-7.56 (4H, m), 8.26 (1H, s), 8.61 (1H, s).

Example 157-((6-(Difluoromethyl)pyridin-2-yl)methyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

3rd Generation BrettPhos precatalyst (22.95 mg, 0.03 mmol) was added to2-(2-chloro-5-methylpyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 51; 205 mg, 0.51 mmol), 1-methyl-1H-pyrazol-5-amine (123mg, 1.27 mmol) and Cs₂CO₃ (330 mg, 1.01 mmol) in 1,4-dioxane (8 mL) at25° C. under nitrogen and the resulting mixture was stirred at 100° C.for 8 hours. The solvent was then removed under reduced pressure. Thecrude product was purified by flash silica chromatography, elutiongradient 0 to 6% MeOH in DCM. Compound containing fractions wereevaporated to dryness to afford a yellow residue. This residue waspurified further by preparative HPLC (XSelect CSH Prep C18 OBD column,5μ silica, 19 mm diameter, 150 mm length), using decreasingly polarmixtures of water (containing 0.03% NH₃) and MeCN as eluents. Fractionscontaining the desired compound were evaporated to dryness to afford7-((6-(difluoromethyl)pyridin-2-yl)methyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 15; 122 mg, 51.8%) as a white solid. ¹H NMR (400 MHz, DMSO, 20°C.) δ 2.50 (3H, s), 3.70 (3H, s), 3.87-3.95 (2H, m), 4.42-4.50 (2H, m),4.87 (2H, s), 6.30 (1H, d), 6.95 (1H, t), 7.33 (1H, d), 7.61 (2H, t),7.94 (1H, s), 8.00 (1H, t), 8.32 (1H, s), 9.24 (1H, s). m/z (ES+),[M+H]+=466.

Intermediate 512-(2-Chloro-5-methylpyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

6-(Difluoromethyl)picolinaldehyde (Intermediate 39; 123 mg, 0.78 mmol)was added to ethyl1-(2-aminoethyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 21; 200 mg, 0.52 mmol), DIPEA (0.274 mL,1.57 mmol) and AcOH (0.090 mL, 1.57 mmol) in DCM (10 mL) at 25° C. undernitrogen. After stirring at 25° C. for 1 hour, sodiumtriacetoxyborohydride (332 mg, 1.57 mmol) was added and the resultingmixture was stirred at 25° C. for 1 hour and then heated at 50° C. for 3hours. The reaction mixture was quenched with saturated NaHCO₃ (20 mL),extracted with DCM (2×75 mL), the combined organic phases were driedover Na₂SO₄, filtered and evaporated to afford a yellow residue. Thecrude product was purified by flash silica chromatography, elutiongradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to drynessto afford2-(2-chloro-5-methylpyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 51; 205 mg, 97%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃, 20° C.) δ 2.74 (3H, d), 3.95-4.04 (2H, m), 4.27-4.39 (2H, m),4.94 (2H, s), 6.43-6.73 (1H, m), 7.57 (2H, d), 7.84 (1H, t), 7.96 (1H,s), 8.42 (1H, s). m/z (ES+), [M+H]+=405.

Example 16(R)-7-((6-(Difluoromethyl)pyridin-2-yl)methyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

3rd Generation BrettPhos precatalyst (30.3 mg, 0.03 mmol) was added to(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 52; 150 mg, 0.33 mmol), 1-methyl-1H-pyrazol-5-amine (81mg, 0.84 mmol) and Cs₂CO₃ (218 mg, 0.67 mmol) in 1,4-dioxane (8 mL) at25° C. under nitrogen and the resulting mixture was stirred at 120° C.for 8 hours. The solvent was then removed under reduced pressure. Theresulting residue was purified by flash silica chromatography, elutiongradient 0 to 6% MeOH in DCM to afford a yellow residue. This residuewas purified further by preparative HPLC (XSelect CSH Prep C18 OBDcolumn, 5μ silica, 19 mm diameter, 150 mm length), using decreasinglypolar mixtures of water (containing 0.03% NH₃) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness toafford(R)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 16; 27 mg, 15.9%) as a white solid. ¹H NMR (400 MHz, DMSO, 25°C.) δ 2.50 (3H, s), 3.20 (3H, s), 3.34-3.42 (1H, m), 3.52 (1H, dd), 3.71(3H, s), 4.15 (1H, s), 4.59 (3H, d), 5.24 (1H, d), 6.28-6.33 (1H, m),6.97 (1H, t), 7.34 (1H, d), 7.59-7.66 (2H, m), 7.95-8.04 (2H, m), 8.32(1H, s), 9.21 (1H, s). m/z (ES+), [M+H]+=510.

Intermediate 52(R)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

A solution of (R)-ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-(2-(((6-(difluoromethyl)pyridin-2-yl)methyl)amino)-3-methoxypropyl)-1H-imidazole-2-carboxylate(Intermediate 53; 360 mg, 0.73 mmol) in NH₃ in MeOH (20 mL, 140.00 mmol)was stirred at 25° C. for 48 hours. The volatiles were then removedunder reduced pressure. The crude product was purified by flash silicachromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractionswere evaporated to dryness to afford(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 52; 300 mg, 92%) as a yellow solid. m/z (ES+), [M+H]+=449.

Intermediate 53 (R)-Ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-(2-(((6-(difluoromethyl)pyridin-2-yl)methyl)amino)-3-methoxypropyl)-1H-imidazole-2-carboxylate

6-(Difluoromethyl)picolinaldehyde (442 mg, 2.81 mmol) was added to(R)-ethyl1-(2-amino-3-methoxypropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 54; 400 mg, 0.94 mmol) in DCM (20 mL) at25° C. under nitrogen. After stirring at 40° C. for 3 hours, sodiumtriacetoxyborohydride (596 mg, 2.81 mmol) was added and the resultingmixture was stirred at 25° C. for 3 hours. The reaction mixture wasquenched with saturated NaHCO₃ (20 mL), extracted with DCM (2×50 mL),the organic layer was dried over Na₂SO₄, filtered and evaporated toafford yellow residue. The crude product was purified by flash silicachromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractionswere evaporated to dryness to afford (R)-ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-(2-(((6-(difluoromethyl)pyridin-2-yl)methyl)amino)-3-methoxypropyl)-1H-imidazole-2-carboxylate(Intermediate 53; 360 mg, 78%) as a yellow solid. m/z (ES+), [M+H]+=495.

Intermediate 54 (R)-Ethyl1-(2-amino-3-methoxypropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride

A solution of (R)-ethyl1-(2-((tert-butoxycarbonyl)amino)-3-methoxypropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate(Intermediate 55; 1 g, 2.20 mmol) in 1,4-dioxane/HCl (20 mL) was stirredat 25° C. overnight. The precipitate was collected by filtration, washedwith EtOAc (20 mL) and dried under vacuum to afford (R)-ethyl1-(2-amino-3-methoxypropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate(Intermediate 54; 0.80 g, 85%) as a white solid. ¹H NMR (400 MHz, DMSO,22° C.) δ 1.36 (3H, t), 2.64 (3H, s), 3.48-3.66 (5H, m), 3.85 (1H, s),4.39 (2H, q), 4.64-4.79 (2H, m), 8.36 (2H, s), 8.41 (1H, s), 8.62-8.67(1H, m). m/z (ES+), [M+H]+=354.

Intermediate 55 (R)-Ethyl1-(2-((tert-butoxycarbonyl)amino)-3-methoxypropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate

1M HCl (20 mL, 20.00 mmol) was added to(R)-(tert-butoxycarbonyl)(1-(4-(2-chloro-5-methylpyrimidin-4-yl)-2-(ethoxycarbonyl)-1H-imidazol-1-yl)-3-methoxypropan-2-yl)sulfamicacid (Intermediate 56; 5 g, 9.36 mmol) in EtOH (20 mL) at 25° C. underair and the resulting mixture was stirred at 50° C. for 20 minutes. Thereaction mixture was quenched with saturated NaHCO₃ (50 mL), extractedwith DCM (3×100 mL), the organic phases were dried over Na₂SO₄, filteredand evaporated to afford yellow residue. The crude product was purifiedby flash silica chromatography, elution gradient 0 to 30% EtOAc inpetroleum ether. Pure fractions were evaporated to dryness to afford(R)-ethyl1-(2-((tert-butoxycarbonyl)amino)-3-methoxypropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate(Intermediate 55; 1.0 g, 23.53%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃, 22° C.) δ 1.32 (9H, s), 1.47 (3H, t), 2.71 (3H, s), 3.40 (3H, s),3.51 (2H, qd), 4.24 (1H, d), 4.41-4.57 (3H, m), 4.73 (1H, dd), 5.11 (1H,d), 7.98 (1H, s), 8.41 (1H, s).

Intermediate 56(R)-(tert-Butoxycarbonyl)(1-(4-(2-chloro-5-methylpyrimidin-4-yl)-2-(ethoxycarbonyl)-1H-imidazol-1-yl)-3-methoxypropan-2-yl)sulfamicacid

(S)-tert-Butyl 4-(methoxymethyl)-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide (Intermediate 57; 3.26 g, 12.19 mmol) was added portionwiseto ethyl 4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate(Intermediate 23; 2.5 g, 9.37 mmol), K₂CO₃ (3.89 g, 28.12 mmol) and18-crown-6 (0.496 g, 1.87 mmol) in 1,4-dioxane (30 mL) at 100° C. undernitrogen and the resulting mixture was stirred at 100° C. for 12 hours.The reaction mixture was then filtered and washed with DCM and thesolvent was removed under reduced pressure to afford the desired product(R)-(tert-butoxycarbonyl)(1-(4-(2-chloro-5-methylpyrimidin-4-yl)-2-(ethoxycarbonyl)-1H-imidazol-1-yl)-3-methoxypropan-2-yl)sulfamicacid (5.00 g, 100%) as a yellow oil, which was used directly in the nextstage. m/z (ES+), [M+H]+=534.

Intermediate 57 (S)-tert-Butyl4-(methoxymethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

To a solution of (4S)-tert-butyl4-(methoxymethyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide(Intermediate 58; 3.34 g, 13.29 mmol) in acetonitrile (30 mL) at 0° C.under nitrogen was added sequentially sodium metaperiodate (3.13 g,14.62 mmol), ruthenium(III) chloride (0.276 g, 1.33 mmol) and water(30.0 mL) and then stirred at 0° C. for 3 hours. The reaction mixturewas diluted with water (100 mL) and filtered to remove insolubleinorganic salts. The resulting solution was extracted with ether (2×100mL), washed with brine (2×100 mL) and dried over MgSO₄ to give(S)-tert-butyl 4-(methoxymethyl)-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide (Intermediate 57; 2.86 g, 80%) as an oil. ¹H NMR (500 MHz,CDCl₃, 27° C.) 1.56 (9H, s), 3.41 (3H, s), 3.59 (1H, t), 3.66 (1H, ddd),4.38 (1H, dddd), 4.52-4.67 (2H, m). m/z: ES+ [M+H]+ 268.

Alternative Preparation of Intermediate 57:

A solution of sodium metaperiodate (95 g, 444.49 mmol) and rutheniumchloride (0.349 g, 1.33 mmol) in water (800 mL) was added to a solutionof tert-butyl (4S)-4-(methoxymethyl)-1,2,3-oxathiazolidine-3-carboxylate2-oxide (Intermediate 58; 111.7 g, 444.49 mmol) in acetonitrile (800 mL)at 10° C. The reaction was shown to be complete by ¹H NMR immediatelyafter the addition. The reaction mixture was diluted with MTBE (1000 mL)and the layers were separated. The organic layer was washed water (2×500mL) and concentrated to afford (S)-tert-butyl4-(methoxymethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(Intermediate 57; 115 g, 95%) as an oil. ¹H NMR (400 MHz, MeOD) δ 1.54(s, 9H), 3.40 (s, 3H), 3.61 (d, 2H), 4.46 (qd, 1H), 4.60 (dd, 1H), 4.68(dd, 1H).

Intermediate 58 (4S)-tert-Butyl4-(methoxymethyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide

Imidazole (1.629 g, 23.92 mmol) was added in one portion to thionylchloride (1.75 mL, 23.92 mmol) and triethylamine (3.33 mL, 23.92 mmol)in DCM (100 mL) and cooled to −78° C. under nitrogen. The resultingsolution was stirred for 20 minutes. A solution of (R)-tert-butyl(1-hydroxy-3-methoxypropan-2-yl)carbamate (Intermediate 59; 4.91 g,23.92 mmol) in DCM (26.7 mL) was added dropwise over 10 minutes. Theresulting solution was stirred at −78° C. for 3 hours and then allowedto warm to room temperature. To the reaction mixture was added water(100 mL), and then extracted with DCM (2×100 mL). The organics werecombined and washed with brine (100 mL), dried over MgSO₄ and evaporatedto afford a crude product. The crude product was purified by flashsilica chromatography, eluting with 10% Et₂O in DCM. Pure fractions wereevaporated to dryness to afford (4S)-tert-butyl4-(methoxymethyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide(Intermediate 58; 3.34 g, 55.6%) as a colourless oil and as a 2:1mixture of diastereomers. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.55-1.58 (9H,d), 3.31 (0.5H, t), 3.41 (3H, s), 3.52-3.63 (1H, m), 3.90 (0.5H, dd),4.17-4.4 (1H, m), 4.64-4.92 (1H, m), 4.94-5.07 (1H, m). m/z: ES+ [M+H]+252.

Alternative Preparation of Intermediate 58:

To a solution of 1H-imidazole (672 g, 9.76 mol) in dichloromethane (5 L)was added triethylamine (568 g, 5.61 mol) and the resulting solution wascooled to −60° C. Thionyl chloride (377 g, 3.17 mol) was added dropwiseto the mixture maintaining a temperature below −50° C. (2 h).(R)-tert-Butyl (1-hydroxy-3-methoxypropan-2-yl)carbamate (Intermediate59; 500 g, 2.44 mol) dissolved in dichloromethane (5 L) was then addeddropwise over the course of 4 to 5 hours keeping the temperature below−55° C. throughout the addition. Once all the starting material isadded, the reaction was left to warm to room temperature overnight. Thereaction mixture was then poured into water (˜3 L), the layersseparated, and the aqueous layer extracted with DCM (1 L). The combinedorganic layers were dried over MgSO4, and the mixture filtered through aplug of silica (2 Kg) eluting with dichloromethane, and concentratedunder reduced pressure to give an oil. This oil was placed under highvacuum with stirring to remove residual dichloromethane to give(4S)-tert-butyl 4-(methoxymethyl)-1,2,3-oxathiazolidine-3-carboxylate2-oxide (Intermediate 58; 489 g, 80%) as an oil and as a 36:64 mixtureof diastereomers.

Intermediate 59 (R)-tert-Butyl (1-hydroxy-3-methoxypropan-2-yl)carbamate

iso-Butyl chloroformate (0.599 mL, 4.56 mmol) was added dropwise to(S)-2-((tert-butoxycarbonyl)amino)-3-methoxypropanoic acid (1 g, 4.56mmol) and N-methylmorpholine (0.501 mL, 4.56 mmol) in THF (6 mL) andcooled to 0° C. over a period of 15 minutes under nitrogen. Theresulting suspension was stirred at 0° C. for a further 15 minutes.Sodium borohydride (0.500 g, 13.23 mmol) dissolved in water (1.2 mL) wasadded slowly to the reaction at 0° C. The reaction was stirred for 30minutes before being diluted with EtOAc (50 mL) and neutralised withaqueous HCl (2M). Water was added (50 mL) and the organic layer wasseparated, washed with brine (50 mL) and dried over MgSO₄. Theevaporation of the solvent gave a crude product which was purified byflash silica chromatography, elution gradient 0 to 50% EtOAc in heptane.Pure fractions were evaporated to dryness to afford (R)-tert-butyl(1-hydroxy-3-methoxypropan-2-yl)carbamate (Intermediate 59; 0.510 g,54.5%) as a colourless oil. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.45 (9H,s), 3.36 (3H, s), 3.5-3.62 (2H, m), 3.64-3.73 (1H, m), 3.74-3.84 (2H,m), 5.16 (1H, s). m/z: ES+ [M+Na]+228.

Example 17(R)-7-(3-Chlorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

2nd Generation XantPhos precatalyst (30.8 mg, 0.03 mmol) was added to(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3-chlorobenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 60; 150 mg, 0.35 mmol), 1-methyl-1H-pyrazol-5-amine (84mg, 0.87 mmol) and Cs₂CO₃ (226 mg, 0.69 mmol) in 1,4-dioxane (5 mL) at25° C. under nitrogen. The resulting mixture was stirred at 100° C. for8 hours. The solvent was then removed under reduced pressure. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 6% MeOH in DCM. Product containing fractions were evaporated todryness to afford a yellow residue. This residue was purified further bypreparative HPLC (XSelect CSH Prep C18 OBD column, 5μ silica, 19 mmdiameter, 150 mm length), using decreasingly polar mixtures of water(containing 0.03% NH₃) and MeCN as eluents. Fractions containing theproduct were evaporated to dryness to afford(R)-7-(3-chlorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 17; 34.0 mg, 19.9%) as a white solid. ¹H NMR (400 MHz, DMSO,24° C.) δ 2.51 (3H, s), 3.18 (3H, s), 3.29 (1H, s), 3.40 (1H, dd), 3.70(3H, s), 4.04 (1H, s), 4.39-4.57 (3H, m), 5.09 (1H, d), 6.30 (1H, d),7.31-7.50 (5H, m), 7.94 (1H, s), 8.32 (1H, s), 9.21 (1H, s). m/z (ES+),[M+H]+=493.

Intermediate 60(R)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3-chlorobenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

1-(Bromomethyl)-3-chlorobenzene (187 mg, 0.91 mmol) was added to(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 61; 140 mg, 0.45 mmol) and NaH (54.6 mg, 1.36 mmol) in DMF(5 mL) at 25° C. under nitrogen and the resulting mixture was stirred at25° C. for 12 hours. The reaction mixture was quenched with water (25mL) and extracted with EtOAc (3×25 mL). The combined organic phases werewashed with brine, dried over Na₂SO₄, filtered and evaporated to affordyellow residue. The crude product was purified by flash silicachromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractionswere evaporated to dryness to afford(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3-chlorobenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 60; 150 mg, 76%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃, 25° C.) δ 2.81 (3H, s), 3.30 (4H, s), 3.41 (1H, s), 3.84 (1H, s),4.17-4.28 (2H, m), 4.43 (1H, d), 5.44 (1H, d), 7.33 (2H, d), 7.40 (2H,s), 7.97 (1H, s), 8.04 (1H, s). m/z (ES+), [M+H]+=432.

Intermediate 61(R)-2-(2-Chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

A solution of (R)-ethyl1-(2-amino-3-methoxypropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 54; 400 mg, 0.94 mmol) in NH₃ in MeOH (15mL, 105.00 mmol) was stirred at 25° C. overnight. The solvent was thenremoved under reduced pressure. The crude product was purified by flashsilica chromatography, elution gradient 0 to 5% MeOH in DCM. Purefractions were evaporated to dryness to afford(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 61; 280 mg, 97%) as a white solid. ¹H NMR (400 MHz, CDCl₃,23° C.) δ 2.78 (3H, s), 3.43 (3H, s), 3.49-3.58 (2H, m), 4.16-4.33 (2H,m), 4.37 (1H, dd), 6.56 (1H, s), 8.01 (1H, s), 8.45 (1H, s). m/z (ES+),[M+H]+=308.

Alternative Preparation of Intermediate 61:

A solution of tert-butyl(S)-4-(methoxymethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(Intermediate 57; 105 g, 383.60 mmol) in acetone (500 mL) was added to astirred suspension of ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate(Intermediate 23; 93 g, 348.73 mmol) and K₂CO₃ (57.8 g, 418.47 mmol) ina mixture of acetone (500 mL) and 1,4 dioxane (500 mL) at roomtemperature. The resulting mixture was stirred at 25° C. for 16 hours.The reaction mixture was filtered and the filtrate was concentrated to500 mL. To the concentrated solution, HCl in iso-propylalcohol (5-6N,500 mL, 2500 mmol) was added and stirred at 25° C. for 24 hours. Et₃N(486 mL, 3487.26 mmol) was then added to the mixture and stirred at 55°C. for 16 hours. The reaction mixture was quenched with water (1500 mL)and resulting solid was filtered. The solid cake was washed with a water(400 mL) and 1:1 mixture of acetone/water (200 mL×2) to afford(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one (82 g, 76%) as a solid. ¹H NMR (400 MHz, DMSO,20° C.) δ 2.62 (s, 3H), 3.27 (s, 3H), 3.39 (dd, 2H), 3.99 (s, 1H), 4.30(dd, 1H), 4.43 (dd, 1H), 8.26 (s, 1H), 8.42 (d, 1H), 8.59 (s, 1H). m/z(ES+), [M+H]+=308.

Example 18(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

2nd Generation XantPhos precatalyst (0.784 g, 0.86 mmol) was added to(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 62; 7.5 g, 17.29 mmol), 1-methyl-1H-pyrazol-5-amine (4.20g, 43.22 mmol) and Cs₂CO₃ (11.27 g, 34.58 mmol) in 1,4-dioxane (200 mL)at 25° C. under nitrogen. The resulting mixture was stirred at 100° C.for 8 hours. The solvent was then removed under reduced pressure. Thecrude product was purified by flash silica chromatography, elutiongradient 0 to 6% MeOH in DCM. Product containing fractions wereevaporated to dryness to afford a residue. This residue was purifiedfurther by C18-flash chromatography, elution gradient 5 to 50% MeCN inwater (0.1% NH₄HCO₃). Pure fractions were evaporated to dryness toafford(R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 18; 5.50 g, 64.3%) as a solid.(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-onewas determined to be amorphous by XRPD.

Alternative Preparation of Example 18:

To a mixture of(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 62; 104.7 g, 225.64 mmol), 1-methyl-1H-pyrazol-5-amine(33.5 g, 338.47 mmol) in 2-methyl tetrahydrofuran (1200 mL) and Cs₂CO₃(147 g, 451.29 mmol) in water (120 mL) were added2′-(dicyclohexylphosphanyl)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (7.10g, 18.05 mmol) and Pd₂(dba)₃ (8.27 g, 9.03 mmol) at 25° C. undernitrogen. The resulting mixture was degassed 3 times under nitrogen andthen stirred at 70° C. for 24 hours. The reaction mixture was cooled toroom temperature and the layers were separated. The organic layer waswashed successively with water (500 mL), aqueous citric acid (1N, 600mL) and water (200 mL). Silicycle (Si—SH, 150 g) was added to theorganic layer at 40° C. and stirred for hours. After filtration thefiltrate was concentrated and the residue was purified by SFCchromatography using a Kromasil DIOL column, elution gradient 25%EtOH/NH₃ 100/0.5 in CO₂, 140 bar. Pure fractions were evaporated todryness to afford(R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 18; 72.6 g, 65%) as a solid. ¹H NMR (500 MHz, DMSO) δ 2.51 (3H,s), 3.17 (3H, s), 3.30 (1H, dd), 3.39 (1H, dd), 3.69 (3H, s), 4.03 (1H,dtd), 4.38 (1H, d), 4.44 (1H, dd), 4.51 (1H, dd), 5.08 (1H, d), 6.30(1H, d), 7.22-7.28 (1H, m), 7.33 (1H, d), 7.41 (1H, dt), 7.47 (1H, ddd),7.93 (1H, s), 8.31 (1H, s), 9.21 (1H, s). m/z (ES+), [M+H]+=495.

Example 18a Preparation of(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one Ethanesulfonic acid adduct Form 1

To a hot solution of(R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 18; 114 g, 200.56 mmol) in MeCN (500 mL) at 55° C. was added asolution of ethanesulfonic acid (17.02 mL, 210.59 mmol) in acetonitrile(100 mL). The reaction mixture was slowly cooled to 5° C. over 24 hours,the resulting solid was filtered and washed with cold MeCN (200 mL) toafford the ethanesulfonic acid adduct Form 1 of(R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneForm 1 (Example 18a; 119 g, 98%) as a solid. The adduct was determinedby ¹H NMR to be a 1:1 molar ratio of ethanesulfonicacid:(R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one.¹H NMR (400 MHz, DMSO, 24° C.) δ 1.08 (3H, t), 2.44-2.49 (2H, m), 2.51(3H, s), 3.16 (3H, s), 3.32 (1H, dd), 3.41 (1H, dd), 3.76 (3H, s),3.97-4.12 (1H, m), 4.32-4.62 (3H, m), 5.08 (1H, d), 6.48 (1H, d),7.17-7.30 (1H, m), 7.34-7.52 (2H, m), 7.55 (1H, d), 8.04 (1H, s), 8.39(1H, s), 9.67 (1H, s).(R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneethanesulfonic acid adduct Form 1 was determined to be crystalline byXRPD (FIG. 1) and had a melting point of 203.8° C. (onset) (FIG. 2).

Intermediate 62(R)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

4-(Bromomethyl)-1,2-difluorobenzene (6.05 g, 29.25 mmol) was added to(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one (Intermediate 61; 6 g, 19.50mmol) and NaH (2 g, 50. mmol) in DMF (80 mL) at 25° C. under nitrogen.The resulting mixture was stirred at 25° C. for 2 hours. The reactionmixture was quenched with saturated NaHCO₃ (400 mL), extracted withEtOAc (3×250 mL), the organic layers were washed with brine, dried overNa₂SO₄, filtered and evaporated to afford a yellow residue. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 62; 8.00 g, 95%) as a light yellow solid. ¹H NMR (300 MHz,CDCl₃) δ 2.76 (3H, s), 3.25-3.35 (1H, m), 3.28 (3H, s), 3.35-3.42 (1H,m), 3.78-3.85 (1H, m), 4.18-4.26 (2H, m), 4.42 (1H, d), 5.34 (1H, d),7.08-7.30 (3H, m), 7.95 (1H, s), 8.43 (1H, s). m/z (ES+), [M+H]+=434.

Alternative Preparation of Intermediate 62:

Cs₂CO₃ (115 g, 354.44 mmol) was added to(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 61: 79.5 g, 253.17 mmol) in MeCN (800 mL) at 25° C. undernitrogen. The resulting mixture was heated to 40° C. and MeCN (100 mL)was distilled off. 4-(Bromomethyl)-1,2-difluorobenzene (64.2 g, 303.80mmol) was added at 60° C. and stirred at 60-70° C. for 20 hours. Thereaction mixture was concentrated to 500 mL and diluted with EtOAc (1000mL) and water (500 mL). The layers were separated and the organic layerwas washed water (2×500 mL) and the volatiles removed under reducedpressure. The residue was stirred in a mixture of MTBE (120 mL) andHeptane (480 mL) at 40° C., the resulting solid was filtered and washedwith heptane (250 mL) to afford(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(100 g, 91%) as a solid. ¹H NMR (400 MHz, DMSO, 24° C.) δ 2.37 (3H, s),3.04 (3H, s), 3.11-3.19 (1H, m), 3.28 (1H, dd), 3.92 (1H, m), 4.27 (1H,d), 4.35 (2H d), 4.95 (1H, d), 7.06-7.22 (1H, m), 7.22-7.48 (2H, m),8.13 (1H, s), 8.47 (s, 1H). m/z (ES+), [M+H]+=434.

Example 19(S)-7-(3-Chlorobenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

2nd Generation XantPhos precatalyst (33.1 mg, 0.04 mmol) was added to(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3-chlorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 63; 150 mg, 0.37 mmol), 1-methyl-1H-pyrazol-5-amine (91mg, 0.93 mmol) and Cs₂CO₃ (243 mg, 0.75 mmol) in 1,4-dioxane (5 mL) at25° C. under nitrogen. The resulting mixture was stirred at 100° C. for4 hours. The solvent was then removed under reduced pressure. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford ayellow residue. This residue was purified further by preparative HPLC(XSelect CSH Prep C18 OBD column, 5 silica, 19 mm diameter, 150 mmlength), using decreasingly polar mixtures of water (containing 0.03%NH₃) and MeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford(S)-7-(3-chlorobenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 19; 71.0 mg, 41.1%) as a white solid. ¹H NMR (400 MHz, DMSO,24° C.) δ1.14 (3H, d), 2.53 (3H, s), 3.70 (3H, s), 4.00 (1H, s),4.30-4.48 (3H, m), 5.07 (1H, d), 6.30 (1H, d), 7.31-7.45 (4H, m), 7.48(1H, s), 7.93 (1H, s), 8.33 (1H, s), 9.22 (1H, s). m/z (ES+),[M+H]+=463.

Intermediate 63(S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3-chlorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

1-(Bromomethyl)-3-chlorobenzene (1332 mg, 6.48 mmol) was added to(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 64; 300 mg, 1.08 mmol) and NaH (259 mg, 6.48 mmol) in DMF(10 mL) at 25° C. under nitrogen. The resulting mixture was stirred at25° C. for 2 hours. The reaction mixture was quenched with water (25mL), extracted with EtOAc (2×25 mL), the organic layers were washed withbrine and dried over Na₂SO₄, filtered and evaporated to afford a yellowresidue. The crude product was purified by flash silica chromatography,elution gradient 10 to 60% EtOAc in petroleum ether. Pure fractions wereevaporated to dryness to afford(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3-chlorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 63; 300 mg, 69.0%) as a white solid. ¹H NMR (400 MHz,CDCl₃, 22° C.) δ 1.24-1.34 (3H, m), 2.81 (3H, s), 3.84-3.92 (1H, m),4.03-4.19 (2H, m), 4.37 (1H, dd), 5.45 (1H, d), 7.27 (1H, d), 7.30-7.34(2H, m), 7.38 (1H, s), 7.99 (1H, s), 8.45 (1H, s). m/z (ES+),[M+H]+=402.

Intermediate 64(S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

A solution of (S)-ethyl1-(2-aminopropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 65; 2.8 g, 7.77 mmol) in NH₃ (7N in MeOH,20 mL, 140 mmol) was stirred at 25° C. overnight. The solvent wasremoved under reduced pressure to afford the desired product(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(2.1 g, 97%) as a white solid, which was used in the next step withoutpurification. m/z (ES+), [M+H]+=278.

Intermediate 65 (S)-Ethyl1-(2-aminopropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride

A solution of (S)-ethyl1-(2-((tert-butoxycarbonyl)amino)propyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate(Intermediate 66; 3.4 g, 8.02 mmol) in 33% HCl (gas) in EtOH (20 mL) wasstirred at 25° C. overnight. The solvent was removed under reducedpressure to afford the desired product (S)-ethyl1-(2-aminopropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 65; 2.80 g, 97%) as a white solid. ¹H NMR(400 MHz, DMSO, 24° C.) δ 1.28 (3H, d), 1.35 (3H, t), 2.64 (3H, s), 3.74(1H, s), 4.39 (2H, q), 4.58-4.76 (2H, m), 8.37 (2H, s), 8.47 (1H, s),8.61-8.67 (1H, m). m/z (ES+), [M+H]+=324.

Intermediate 66 (S)-Ethyl1-(2-((tert-butoxycarbonyl)amino)propyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate

1M HCl (20 mL, 20.00 mmol) was added to(S)-(tert-butoxycarbonyl)(1-(4-(2-chloro-5-methylpyrimidin-4-yl)-2-(ethoxycarbonyl)-1H-imidazol-1-yl)propan-2-yl)sulfamicacid (Intermediate 67; 5 g, 9.92 mmol) in EtOH (20 mL) at 25° C. underair. The resulting mixture was stirred at 50° C. for 20 minutes. Thereaction mixture was quenched with saturated NaHCO₃ (50 mL), extractedwith DCM (3×100 mL), the organic layer was dried over Na₂SO₄, filteredand evaporated to afford a yellow residue. The crude product waspurified by flash silica chromatography, elution gradient 0 to 30% EtOAcin petroleum ether. Pure fractions were evaporated to dryness to afford(S)-ethyl1-(2-((tert-butoxycarbonyl)amino)propyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate(Intermediate 66; 3.40 g, 81%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃, 24° C.) δ 1.27 (3H, dd), 1.35 (9H, s), 1.48 (3H, t), 2.72 (3H,s), 4.09-4.18 (1H, m), 4.47 (3H, qd), 4.64 (2H, dd), 8.01 (1H, s), 8.42(1H, s). m/z (ES+), [M+H]+=424.

Intermediate 67(S)-(tert-Butoxycarbonyl)(1-(4-(2-chloro-5-methylpyrimidin-4-yl)-2-(ethoxycarbonyl)-1H-imidazol-1-yl)propan-2-yl)sulfamicacid

(S)-tert-Butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(Intermediate 12; 3.34 g, 14.06 mmol) was added portionwise to ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate(Intermediate 23; 3 g, 11.25 mmol) and K₂CO₃ (3.11 g, 22.50 mmol) inacetonitrile (3 mL) at 80° C. under nitrogen. The resulting mixture wasstirred at 85° C. for 4 hours. The reaction mixture was filtered andwashed with MeCN, the solvent was removed under reduced pressure toafford the desired product(S)-(tert-butoxycarbonyl)(1-(4-(2-chloro-5-methylpyrimidin-4-yl)-2-(ethoxycarbonyl)-1H-imidazol-1-yl)propan-2-yl)sulfamicacid (5.00 g, 88%) as a yellow oil. m/z (ES+), [M+H]+=504.

Example 20(S)-7-(3,4-Difluorobenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 68; 189 mg, 0.47 mmol), 1-methyl-1H-pyrazol-5-amine (91mg, 0.94 mmol), Cs₂CO₃ (457 mg, 1.40 mmol) and 3rd Generation BrettPhosprecatalyst (42.4 mg, 0.05 mmol) in 1,4-dioxane (5 mL) was stirred underan atmosphere of nitrogen at 110° C. for 8 hours. The solvent wasremoved by distillation under vacuum. The crude product was purified byflash silica chromatography, elution gradient 4 to 5% MeOH in DCM. Purefractions were evaporated to dryness to afford a yellow solid. The solidwas purified further by preparative HPLC (XSelect CSH Prep C18 OBDcolumn, 5μ silica, 19 mm diameter, 150 mm length), using decreasinglypolar mixtures of water (containing 0.01% NH₄HCO₃) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness toafford(S)-7-(3,4-difluorobenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 20; 63.8 mg, 29.3%) as a white solid. ¹H NMR (400 MHz, DMSO,24.8° C.) δ 1.14 (3H, d), 2.53 (3H, d), 3.70 (3H, s), 3.95-4.03 (1H, m),4.29-4.38 (2H, m), 4.44 (1H, dd), 5.06 (1H, d), 6.30 (1H, d), 7.27 (1H,s), 7.34 (1H, d), 7.37-7.53 (2H, m), 7.93 (1H, s), 8.33 (1H, d), 9.21(1H, s). m/z (ES+), [M+H]+=465.

Intermediate 68(S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

NaH (108 mg, 2.70 mmol) was added to(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 64; 250 mg, 0.90 mmol) in DMF (5 mL) at 0° C. undernitrogen. The resulting solution was stirred at 0° C. for 30 minutes.4-(Bromomethyl)-1,2-difluorobenzene (373 mg, 1.80 mmol) was then addedand the resulting solution was stirred at 20° C. for 12 hours. Thereaction mixture was quenched with water (15 mL), extracted with EtOAc(4×10 mL). The organic layers were combined and washed with water (3×20mL), brine (20 mL). The organic layers were dried over Na₂SO₄, filteredand evaporated to afford yellow oil. The crude product was purified byflash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Purefractions were evaporated to dryness to afford(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 68; 189 mg, 52%) as a yellow solid. m/z (ES+), [M+H]+=404.

Example 21(S)-7-(3-(Difluoromethyl)benzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

BrettPhos 3rd generation precatalyst (12.44 mg, 0.02 mmol) was added toCs₂CO₃ (304 mg, 0.93 mmol), 1-methyl-1H-pyrazol-5-amine (91 mg, 0.93mmol) and(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3-(difluoromethyl)benzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 69; 130 mg, 0.31 mmol) in 1,4-dioxane (5 mL) undernitrogen. The resulting mixture was stirred at 100° C. for 4 hours. Thesolvent was then removed under reduced pressure. The crude product waspurified by flash silica chromatography, elution gradient 0 to 6% MeOHin DCM. Pure fractions were evaporated to dryness to afford a residue.This residue was purified further by preparative HPLC (XSelect CSH PrepC18 OBD column, 5 silica, 19 mm diameter, 150 mm length), usingdecreasingly polar mixtures of water (containing 0.1% Formic acid) andMeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford(S)-7-(3-(difluoromethyl)benzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 21; 85 mg, 57.1%) as a white solid. ¹H NMR (300 MHz, DMSO, 23°C.) δ 1.12 (3H, s), 2.40 (3H, s), 3.70 (3H, s), 3.90-4.10 (1H, m),4.36-4.44 (3H, m), 5.14 (1H, d), 6.29 (1H, d), 7.04 (1H, t), 7.33 (1H,d), 7.50-7.59 (4H, m), 7.93 (1H, s), 8.32 (1H, s), 9.21 (1H, s). m/z(ES+), [M+H]+=479.

Intermediate 69(S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3-(difluoromethyl)benzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

1-(Bromomethyl)-3-(difluoromethyl)benzene (207 mg, 0.94 mmol) was addedto(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 64; 130 mg, 0.47 mmol) and NaH (56.2 mg, 1.40 mmol) in DMF(3 mL). The resulting mixture was stirred at 25° C. for 18 hours. Thereaction mixture was poured into saturated NaHCO₃ (50 mL), extractedwith EtOAc (2×50 mL), the organic layer was dried over Na₂SO₄, filteredand evaporated to afford crude. The crude product was purified by flashsilica chromatography, elution gradient 0 to 4% MeOH in DCM. Purefractions were evaporated to dryness to afford(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3-(difluoromethyl)benzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(130 mg, 66.5%) as a pale yellow oil. m/z (ES+), [M+H]+=418.

Example 22(S)-7-(3,5-Difluorobenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

Brettphos 3rd generation precatalyst (12.88 mg, 0.02 mmol) was added to1-methyl-1H-pyrazol-5-amine (94 mg, 0.97 mmol),(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,5-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 70; 130 mg, 0.32 mmol) and Cs₂CO₃ (315 mg, 0.97 mmol) in1,4-dioxane (5 mL) under nitrogen. The resulting mixture was stirred at100° C. for 4 hours. The solvent was then removed under reducedpressure. The crude product was purified by flash silica chromatography,elution gradient 0 to 7% MeOH in DCM. Pure fractions were evaporated todryness to afford a residue. The crude product was purified further bypreparative HPLC (XSelect CSH Prep C18 OBD column, 5 silica, 19 mmdiameter, 150 mm length), using to decreasingly polar mixtures of water(containing 0.1% Formic acid) and MeCN as eluents. Fractions containingthe desired compound were evaporated to dryness to afford(S)-7-(3,5-difluorobenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 22; 60 mg, 40.1%) as a white solid. ¹H NMR (300 MHz, DMSO, 23°C.) δ 1.15 (3H, d), 2.60 (3H, s), 3.70 (3H, s), 3.90-4.10 (1H, m),4.32-4.38 (2H, m), 4.46-4.52 (1H, dd), 5.08 (1H, d), 6.29 (1H, d),7.12-7.18 (3H, m), 7.33 (1H, s), 7.93 (1H, s), 8.32 (1H, s), 9.21 (1H,s). m/z (ES+), [M+H]+=465.

Intermediate 70(S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3,5-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

1-(Bromomethyl)-3,5-difluorobenzene (194 mg, 0.94 mmol) was added to(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 64; 130 mg, 0.47 mmol) and NaH (37.4 mg, 0.94 mmol) in DMF(3 mL) and the resulting mixture was stirred at 25° C. for 18 hours. Thereaction mixture was poured into saturated NaHCO₃ (50 mL), extractedwith EtOAc (2×50 mL), the organic layers were dried over Na₂SO₄,filtered and evaporated to afford crude product. The crude product waspurified by flash silica chromatography, elution gradient 0 to 4% MeOHin DCM. Pure fractions were evaporated to dryness to afford(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,5-difluorobenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 70; 130 mg, 68.8%) as a pale yellow oil. ¹H NMR (400 MHz,DMSO, 20° C.) δ 1.15 (3H, d), 2.64 (3H, s), 4.02 (1H, s), 4.26-4.42 (2H,m), 4.47-4.57 (1H, m), 5.09 (1H, d), 7.15 (3H, d), 8.27 (1H, s), 8.61(1H, s). m/z (ES+), [M+H]+=404.

Example 23(S)-7-(3-Methoxybenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

(S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3-methoxybenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 71; 193 mg, 0.49 mmol), 1-methyl-1H-pyrazol-5-amine (94mg, 0.97 mmol), Cs₂CO₃ (474 mg, 1.46 mmol) and 3rd Generation BrettPhosprecatalyst (44.0 mg, 0.05 mmol) in 1,4-dioxane (5 mL) was stirred underan atmosphere of nitrogen at 120° C. for 8 hours. The solvent was thenremoved by distillation under vacuum. The crude product was purified byflash silica chromatography, elution gradient 3 to 5% MeOH in DCM,compound containing fractions were evaporated to dryness to afford ayellow solid. This solid was purified further by preparative HPLC(XSelect CSH Prep C18 OBD column, 5 silica, 19 mm diameter, 150 mmlength), using decreasingly polar mixtures of water (containing 0.01%NH₄HCO₃) and MeCN as eluents.

Fractions containing the desired compound were evaporated to dryness toafford(S)-7-(3-methoxybenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 23; 81 mg, 36.2%) as a white solid. ¹H NMR (400 MHz, DMSO,22.4° C.) δ 1.12 (3H, d), 2.53 (3H, d), 3.70 (3H, s), 3.76 (3H, s),3.90-3.99 (1H, m), 4.25-4.44 (3H, m), 5.09 (1H, d), 6.31 (1H, d), 6.87(1H, ddd), 6.92-7.00 (2H, m), 7.29 (1H, t), 7.34 (1H, d), 7.93 (1H, s),8.33 (1H, d), 9.22 (1H, s). m/z (ES+), [M+H]+=459.

Intermediate 71(S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3-methoxybenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

Batch 1: NaH (8.64 mg, 0.22 mmol) was added to(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 64; 20 mg, 0.07 mmol) in DMF (1 mL) at 25° C. undernitrogen. The resulting solution was stirred at 25° C. for 30 minutes.1-(bromomethyl)-3-methoxybenzene (29.0 mg, 0.14 mmol) was added toreaction mixture and the resulting solution was stirred at 25° C. for 2hours. Batch 2: NaH (56.2 mg, 1.40 mmol) was added to(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(130 mg, 0.47 mmol) in DMF (3 mL) at 20° C. under nitrogen. Theresulting solution was stirred at 20° C. for 30 minutes.1-(bromomethyl)-3-methoxybenzene (188 mg, 0.94 mmol) was added toreaction mixture and the resulting solution was stirred at 20° C. for 2hours. The 2 batches of material were combined and the followingprocedure applied to the combined batches: The reaction mixture wasquenched with saturated NaHCO₃ (15 mL) and extracted with EtOAc (3×15mL). The organic layers were combined and washed with water (2×15 mL),brine (15 mL), the organic layer was dried over Na₂SO₄, filtered andevaporated to afford yellow oil. The crude product was purified by flashsilica chromatography, elution gradient 3 to 4% MeOH in DCM. Purefractions were evaporated to dryness to afford(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3-methoxybenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 71; 193 mg, 89%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃,23.0° C.) δ 1.29 (3H, d), 2.81 (3H, s), 3.80-3.93 (4H, m), 3.98-4.13(1H, m), 4.34 (1H, dd), 5.32 (1H, s), 5.50 (1H, d), 6.84-6.99 (3H, m),7.31 (1H, d), 7.97 (1H, s), 8.45 (1H, s). m/z (ES+), [M+H]+=398.

Example 24(S)-7-(4-Fluoro-3-methoxybenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

(S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-(4-fluoro-3-methoxybenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 72; 205 mg, 0.49 mmol), 1-methyl-1H-pyrazol-5-amine (96mg, 0.99 mmol), Cs₂CO₃ (482 mg, 1.48 mmol) and 3rd Generation BrettPhosprecatalyst (44.7 mg, 0.05 mmol) in 1,4-dioxane (5 mL) was stirred underan atmosphere of nitrogen at 120° C. for 8 hours. The solvent was thenremoved by distillation under vacuum. The crude product was purified byflash silica chromatography, elution gradient 3 to 5% MeOH in DCM. Purefractions were evaporated to dryness to afford a yellow solid. Thissolid was purified further by preparative HPLC (XSelect CSH Prep C18 OBDcolumn, 5μ silica, 19 mm diameter, 150 mm length), using decreasinglypolar mixtures of water (containing 0.01% NH₄HCO₃) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness toafford(S)-7-(4-fluoro-3-methoxybenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 24; 59.0 mg, 25.1%) as a white solid. ¹H NMR (400 MHz, DMSO,22.3° C.) δ 1.13 (3H, d), 2.53 (3H, d), 3.70 (3H, s), 3.85 (3H, s), 3.95(1H, dd), 4.23-4.44 (3H, m), 5.10 (1H, d), 6.31 (1H, d), 6.96 (1H, ddd),7.14-7.24 (2H, m), 7.34 (1H, d), 7.93 (1H, s), 8.33 (1H, d), 9.22 (1H,s). m/z (ES+), [M+H]+=477.

Intermediate 72(S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-(4-fluoro-3-methoxybenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

Batch 1: NaH (56.2 mg, 1.40 mmol) was added to(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(130 mg, 0.47 mmol) in DMF (3 mL) at 20° C. under nitrogen. Theresulting solution was stirred at 20° C. for 30 minutes.4-(bromomethyl)-1-fluoro-2-methoxybenzene (205 mg, 0.94 mmol) was addedto reaction mixture and the resulting solution was stirred at 20° C. for2 hours. Batch 2: NaH (8.64 mg, 0.22 mmol) was added to(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(20 mg, 0.07 mmol) in DMF (1 mL) at 20° C. under nitrogen. The resultingsolution was stirred at 20° C. for 30 minutes.4-(bromomethyl)-1-fluoro-2-methoxybenzene (31.6 mg, 0.14 mmol) was addedto reaction mixture and the resulting solution was stirred at 20° C. for2 hours. The 2 batches of material were combined and the followingprocedure applied to the combined batches: The reaction mixture wasquenched with saturated NaHCO₃ (15 mL) and extracted with EtOAc (3×15mL). The organic layers were combined and washed with water (2×15 mL),brine (15 mL) and the organic layers was dried over Na₂SO₄, filtered andevaporated to afford yellow oil. The crude product was purified by flashsilica chromatography, elution gradient 3 to 4% MeOH in DCM. Purefractions were evaporated to dryness to afford(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(4-fluoro-3-methoxybenzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(205 mg, 91%) as a yellow oil. m/z (ES+), [M+H]+=416.

Example 25(S)-7-((6-(Difluoromethyl)pyridin-2-yl)methyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

3rd Generation BrettPhos precatalyst (0.541 g, 0.60 mmol) was added toCs₂CO₃ (11.67 g, 35.81 mmol), 1-methyl-1H-pyrazol-5-amine (3.48 g, 35.81mmol) and(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 73; 5 g, 11.94 mmol) in 1,4-dioxane (100 mL). Theresulting mixture was stirred at 100° C. for 4 hours. The reactionmixture was then filtered and the solvent was removed under reducedpressure. The crude product was purified by flash silica chromatography,elution gradient 0 to 6% MeOH in DCM. Pure fractions were evaporated todryness to afford a residue. This residue was purified further byC18-flash chromatography, elution gradient 5 to 40% MeCN in water(contained 0.1% NH₄CO₃). Pure fractions were evaporated to dryness toafford(S)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 25; 3.50 g, 61.1%) as a white solid. ¹H NMR (300 MHz, DMSO, 23°C.) δ 1.19 (3H, d), 2.45 (3H, s), 2.61 (3H, s), 3.70 (3H, s), 4.03-4.17(1H, m), 4.33-4.41 (1H, dd), 4.45-4.520 (2H, m), 5.22 (1H, d), 6.30 (1H,d), 6.97 (1H, t), 7.34 (1H, d), 7.60-7.69 (2H, m), 7.96 (1H, s),7.97-8.02 (1H, t), 8.33 (1H, s), 9.23 (1H, s); m/z (ES+), [M+H]+=480.

Intermediate 73(S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

Sodium acetate (2.047 g, 24.95 mmol) was added to (S)-ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-(2-(((6-(difluoromethyl)pyridin-2-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate(Intermediate 74; 5.8 g, 12.48 mmol) in ethanol (absolute, 99.5%, 100mL). The resulting mixture was stirred at 70° C. for 18 hours. Thesolvent was then removed under reduced pressure. The crude product waspurified by flash silica chromatography, elution gradient 0 to 5% MeOHin DCM. Pure fractions were evaporated to dryness to afford(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 73; 5.00 g, 96%) as a pale yellow solid. m/z (ES+),[M+H]+=419.

Intermediate 74 (S)-Ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-(2-(((6-(difluoromethyl)pyridin-2-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate

Sodium triacetoxyborohydride (9.62 g, 45.37 mmol) was added to DIPEA(7.92 mL, 45.37 mmol), (S)-ethyl1-(2-aminopropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 65; 6 g, 15.12 mmol),6-(difluoromethyl)picolinaldehyde (3 g, 19.09 mmol) and acetic acid(2.60 mL, 45.37 mmol) in DCM (100 mL). The resulting mixture was stirredat 25° C. for 1 hours. The reaction mixture was poured into saturatedNaHCO₃ (300 mL) and extracted with DCM (2×150 mL). The organic phaseswere dried over Na₂SO₄ and the volatiles removed under reduced pressure.The crude product was purified by flash silica chromatography, elutiongradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to drynessto afford (S)-ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-(2-(((6-(difluoromethyl)pyridin-2-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate(Intermediate 74; 5.8 g, 82%) as a pale yellow oil. m/z (ES+),[M+H]+=465.

Example 26(S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-7-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 75; 60 mg, 0.14 mmol), 1-methyl-1H-pyrazol-5-amine (39.9mg, 0.41 mmol), Cs₂CO₃ (134 mg, 0.41 mmol) and 3rd Generation BrettPhosprecatalyst (12.42 mg, 0.01 mmol) in 1,4-dioxane (2.5 mL) were stirredunder an atmosphere of nitrogen at 120° C. for 8 hours. The solvent wasthen removed by distillation under vacuum. The crude product waspurified by flash silica chromatography, elution gradient 0 to 5% MeOHin DCM. Pure fractions were evaporated to dryness to afford a yellowsolid. This solid was purified further by preparative HPLC (XSelect CSHPrep C18 OBD column, 5 silica, 19 mm diameter, 150 mm length), usingdecreasingly polar mixtures of water (containing 0.01% NH₄HCO₃) and MeCNas eluents. Fractions containing the desired compound were evaporated todryness to afford(S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 26; 21 mg, 30.7%) as a light yellow solid. ¹H NMR (400 MHz,CDCl₃, 25.5° C.) δ 1.44 (3H, d), 2.74 (3H, s), 3.88 (3H, s), 4.21 (1H,dd), 4.30 (1H, t), 4.42 (1H, d), 4.63 (1H, dd), 5.48 (1H, d), 6.38 (1H,d), 7.52 (1H, d), 7.68 (1H, d), 8.09 (1H, s), 8.31 (1H, s), 8.53 (1H,s), 8.90 (1H, d). m/z (ES+), [M+H]+=499.

Intermediate 75(S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-6-methyl-7-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

NH₃ (7N in MeOH, 10 mL) was added to (S)-ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-(2-(((2-(trifluoromethyl)pyrimidin-4-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate(Intermediate 76; 100 mg, 0.21 mmol) at 20° C. under air. The resultingsolution was stirred at 50° C. for 16 hours. The solvent was thenremoved by distillation under vacuum. The crude product was purified byflash silica chromatography, elution gradient 0 to 6% MeOH in DCM. Purefractions were evaporated to dryness to afford(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-7-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 75; 60 mg, 66.3%) as a colourless oil. m/z (ES+),[M+H]+=438.

Intermediate 76 (S)-Ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-(2-(((2-(trifluoromethyl)pyrimidin-4-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate

2-(Trifluoromethyl)pyrimidine-4-carbaldehyde (147 mg, 0.83 mmol) wasadded to (S)-ethyl1-(2-aminopropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 65; 250 mg, 0.69 mmol) in DCM (10 mL)under air. The resulting solution was stirred at 40° C. for 12 hours.Sodium triacetoxyborohydride (441 mg, 2.08 mmol) was added and theresulting solution was stirred at 20° C. for 12 hour. The reaction wasquenched with water (5 mL), and extracted with DCM (5×10 mL). Theorganic phases were dried over Na₂SO₄, filtered and evaporated to affordyellow oil. The crude product was purified by flash silicachromatography, elution gradient 2 to 4% MeOH in DCM. Pure fractionswere evaporated to dryness to afford (S)-ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-(2-(((2-(trifluoromethyl)pyrimidin-4-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate(Intermediate 76; 110 mg, 32.8%) as a colourless oil. m/z (ES+),[M+H]+=484.

Example 27(S)-6-Methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

3rd Generation BrettPhos precatalyst (11.90 mg, 0.01 mmol) was added to1-methyl-1H-pyrazol-5-amine (87 mg, 0.89 mmol), Cs₂CO₃ (291 mg, 0.89mmol) and(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 77; 130 mg, 0.30 mmol) in 1,4-dioxane (5 mL) undernitrogen. The resulting mixture was stirred at 100° C. for 4 hours. Thesolvent was then removed under reduced pressure. The crude product waspurified by flash silica chromatography, elution gradient 0 to 6% MeOHin DCM, product containing fraction were evaporated to afford a solid.This solid was purified further by preparative HPLC (XSelect CSH PrepC18 OBD column, 5 silica, 19 mm diameter, 150 mm length), usingdecreasingly polar mixtures of water (containing 0.1% Formic acid) andMeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford(S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 27; 100 mg, 67.5%) as a white solid. ¹H NMR (300 MHz, DMSO, 23°C.) δ 1.20 (3H, d), 2.56 (3H, s), 3.70 (3H, s), 4.05-4.18 (1H, m),4.37-4.41 (1H, m), 451-4.60 (2H, m), 5.212 (1H, d), 6.30 (1H, d), 7.34(1H, d), 7.76-7.83 (2H, m), 7.96 (1H, s), 8.06-8.11 (1H, m), 8.32 (1H,s). m/z (ES+), [M+H]+=498.

Intermediate 77(S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-6-methyl-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

(S)-Ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-(2-(((6-(trifluoromethyl)pyridin-2-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate(Intermediate 78; 140 mg, 0.29 mmol) was added to NH₃ (7N in MeOH)solution (10 mL) and the resulting mixture was stirred at 50° C. for 5hours. The solvent was removed under reduced pressure. This afforded(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 77; 110 mg, 87%) as white solid. m/z (ES+), [M+H]+=437.

Intermediate 78 (S)-Ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-(2-(((6-(trifluoromethyl)pyridin-2-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate

6-(Trifluoromethyl)picolinaldehyde (110 mg, 0.63 mmol) was added to(S)-ethyl1-(2-aminopropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 64; 250 mg, 0.63 mmol) in DCM (15 mL) andthe resulting mixture was stirred at 40° C. for 4 hours. After beingcooled to room temperature, sodium triacetoxyborohydride (267 mg, 1.26mmol) was added and the reaction stirred for 1 hour. The reaction wasthen quenched with saturated NaHCO₃ (50 mL) and extracted with DCM (2×50mL). The organic layers were dried over Na₂SO₄, filtered and evaporatedto afford pale yellow oil. The crude product was purified by flashsilica chromatography, elution gradient 0 to 5% MeOH in DCM. Purefractions were evaporated to dryness to afford (S)-ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-(2-(((6-(trifluoromethyl)pyridin-2-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate(Intermediate 78; 140 mg, 46%) as a pale yellow oil. m/z (ES+),[M+H]+=483.

Example 28(S)-7-(3-(Difluoromethoxy)benzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

3rd Generation BrettPhos precatalyst (11.99 mg, 0.01 mmol) was added to1-methyl-1H-pyrazol-5-amine (87 mg, 0.90 mmol),(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3-(difluoromethoxy)benzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 79, 130 mg, 0.30 mmol) in 1,4-dioxane (5 mL) undernitrogen and the resulting mixture was stirred at 100° C. for 4 hours.The solvent was then removed under reduced pressure. The crude productwas purified by flash silica chromatography, elution gradient 0 to 7%MeOH in DCM, compound containing fractions were evaporated to afford asolid. This solid was purified further by preparative HPLC (XSelect CSHPrep C18 OBD column, 5μ silica, 19 mm diameter, 150 mm length), usingdecreasingly polar mixtures of water (containing 0.1) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford(S)-7-(3-(difluoromethoxy)benzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 28; 80 mg, 54%) as a white solid. ¹H NMR (300 MHz, DMSO, 23°C.) δ 1.11 (3H, d), 2.60 (3H, s), 3.70 (3H, s), 3.90-4.10 (1H, m),4.31-4.45 (3H, m), 5.10 (1H, d), 6.29 (1H, d), 7.00-7.50 (4H, m), 7.92(1H, s), 7.83 (1H, s), 8.21 (1H, s), 8.32 (1H, s), 9.21 (1H, s). m/z(ES+), [M+H]+=495.

Intermediate 79(S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3-(difluoromethoxy)benzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

3-(Difluoromethoxy)benzaldehyde (108 mg, 0.63 mmol) was added to(S)-ethyl1-(2-aminopropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 64; 250 mg, 0.63 mmol) in DCM (15 mL) andthe resulting mixture was stirred at 40° C. for 4 hours. Sodiumtriacetoxyborohydride (267 mg, 1.26 mmol) was then added and thereaction stirred for a further 1 hour. The reaction mixture was thenpoured into saturated NaHCO₃ (50 mL) and extracted with DCM (2×50 mL).The combined organic phases were dried over Na₂SO₄, filtered andevaporated to afford crude. The crude product was purified by flashsilica chromatography, elution gradient 0 to 5% MeOH in DCM. Purefractions were evaporated to dryness to afford a white solid. This solidwas then treated with NH₃ (7N in MeOH, 15.00 mL) and heated for 5 hourat 50° C. The volatiles were then removed under reduced pressure toafford(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3-(difluoromethoxy)benzyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(130 mg, 47.5%) as light yellow oil. m/z (ES+), [M+H]+=434.

Example 29(S)-6-Methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((4-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

3rd Generation BrettPhos precatalyst (31.1 mg, 0.03 mmol) was added to(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-7-((4-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 80; 300 mg, 0.69 mmol), 1-methyl-1H-pyrazol-5-amine (167mg, 1.72 mmol) and Cs₂CO₃ (448 mg, 1.37 mmol) in 1,4-dioxane (8 mL) at25° C. under nitrogen. The resulting mixture was stirred at 100° C. for8 hours. The solvent was then removed under reduced pressure. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 6% MeOH in DCM.

Compound containing fractions were evaporated to dryness to afford ayellow residue. This residue was purified further by preparative HPLC(XSelect CSH Prep C18 OBD column, 5μ silica, 19 mm diameter, 150 mmlength), using decreasingly polar mixtures of water (containing 0.03%NH₃) and MeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford(S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((4-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 28; 141 mg, 41.3%) as a white solid. ¹H NMR (400 MHz, DMSO, 20°C.) δ 1.21 (3H, d), 2.52 (3H, s), 3.71 (3H, s), 4.13 (1H, dd), 4.37 (1H,dd), 4.52 (1H, dd), 4.58 (1H, d), 5.26 (1H, d), 6.31 (1H, d), 7.34 (1H,d), 7.71 (1H, d), 7.82 (1H, s), 7.95 (1H, s), 8.33 (1H, s), 8.84 (1H,d), 9.24 (1H, s). m/z (ES+), [M+H]+=498.

Intermediate 80(S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-6-methyl-7-((4-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

4-(Trifluoromethyl)picolinaldehyde (136 mg, 0.78 mmol) was added to(S)-ethyl1-(2-aminopropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 64; 280 mg, 0.71 mmol), DIPEA (0.37 mL,2.12 mmol) and AcOH (0.121 mL, 2.12 mmol) in DCM (10 mL) at 25° C. undernitrogen. After stirring at 25° C. for 1 hour, sodiumtriacetoxyborohydride (449 mg, 2.12 mmol) was added and the resultingmixture was stirred at 25° C. for 2 hours and then heated at 50° C. for8 hours. The reaction mixture was quenched with saturated NaHCO₃ (20 mL)and extracted with DCM (2×75 mL). The combined organic layer was driedover Na₂SO₄, filtered and evaporated afford yellow residue. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-7-((4-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 80; 300 mg, 97%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃, 20° C.) δ 1.60 (3H, s), 2.79 (3H, s), 4.07-4.20 (1H, m), 4.26(1H, s), 4.36-4.45 (1H, m), 4.50 (1H, dd), 5.54 (1H, d), 7.49 (1H, d),7.72 (1H, s), 8.00 (1H, s), 8.45 (1H, s), 8.75 (1H, d).

Example 30(S)-6-Methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((2-(trifluoromethyl)pyridin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

3rd Generation BrettPhos precatalyst (31.1 mg, 0.03 mmol) was added to(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-7-((2-(trifluoromethyl)pyridin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 81; 300 mg, 0.69 mmol), 1-methyl-1H-pyrazol-5-amine (167mg, 1.72 mmol) and Cs₂CO₃ (448 mg, 1.37 mmol) in 1,4-dioxane (8 mL) at25° C. under nitrogen. The resulting mixture was stirred at 100° C. for5 hours. The solvent was then removed under reduced pressure. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 6% MeOH in DCM. Compound containing fractions were evaporated todryness to afford a yellow residue. This residue was purified further bypreparative HPLC (XSelect CSH Prep C18 OBD column, 5μ silica, 19 mmdiameter, 150 mm length), using decreasingly polar mixtures of water(containing 0.03% NH₃) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford(S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((2-(trifluoromethyl)pyridin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 30; 200 mg, 58.5%) as a white solid. ¹H NMR (300 MHz, DMSO, 23°C.) δ 1.18 (3H, d), 2.61 (3H, s), 3.70 (3H, s), 4.00-4.13 (1H, m),4.30-4.40 (1H, d), 4.45-4.60 (2H, m), 5.18 (1H, d), 6.30 (1H, s), 6.20(1H, d), 7.73 (1H, d), 7.91 (1H, s), 7.96 (1H, s), 8.33 (1H, s), 8.73(1H, d), 9.23 (1H, s). m/z (ES+), [M+H]+=498.

Intermediate 81(S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-6-methyl-7-((2-(trifluoromethyl)pyridin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

2-(Trifluoromethyl)isonicotinaldehyde (170 mg, 0.97 mmol) was added to(S)-ethyl1-(2-aminopropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 64; 350 mg, 0.88 mmol), DIPEA (0.462 mL,2.65 mmol) and AcOH (0.152 mL, 2.65 mmol) in DCM (15 mL) at 25° C. undernitrogen. After stirring at 25° C. for 1 hour, sodiumtriacetoxyborohydride (561 mg, 2.65 mmol) was added and the resultingmixture was stirred at 25° C. for 1 hour and heated at 50° C. for 18hours. The reaction mixture was quenched with saturated NaHCO₃ (50 mL)and extracted with DCM (2×75 mL). The organic phases were dried overNa₂SO₄, filtered and evaporated to afford yellow residue. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-7-((2-(trifluoromethyl)pyridin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(320 mg, 83%) as a yellow oil. m/z (ES+), [M+H]+=437.

Example 31(S)-7-((4-(Difluoromethyl)pyridin-2-yl)methyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

3rd Generation BrettPhos precatalyst (51.9 mg, 0.06 mmol) was added to(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-((4-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 82; 240 mg, 0.57 mmol), 1-methyl-1H-pyrazol-5-amine (111mg, 1.15 mmol) and Cs₂CO₃ (373 mg, 1.15 mmol) in 1,4-dioxane (5 mL) at25° C. under nitrogen. The resulting solution was stirred at 120° C. for8 hours. The solvent was then removed by distillation under vacuum. Thecrude product was purified by flash silica chromatography, elutiongradient 4 to 6% MeOH in DCM. Product containing fractions wereevaporated to dryness to afford a solid. This solid was purified furtherby preparative HPLC (XSelect CSH Prep C18 OBD column, 5 silica, 19 mmdiameter, 150 mm length), using decreasingly polar mixtures of water(containing 0.05% NH₄HCO₃) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford(S)-7-((4-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 31; 92 mg, 33.5%) as a white solid. ¹H NMR (400 MHz, CDCl₃,20.2° C.) δ 1.36 (3H, d), 2.69 (3H, s), 3.82 (3H, s), 4.09 (1H, dd),4.22 (1H, tt), 4.37-4.49 (2H, m), 5.50 (1H, d), 6.31 (1H, d), 6.64 (1H,t), 7.01 (1H, s), 7.36-7.43 (1H, m), 7.50 (1H, d), 7.61 (1H, s), 7.75(1H, s), 8.29 (1H, s), 8.69 (1H, d). m/z (ES+), [M+H]+=480.

Intermediate 82(S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-((4-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

4-(Difluoromethyl)picolinaldehyde (Intermediate 83; 154 mg, 0.98 mmol)was added to (S)-ethyl1-(2-aminopropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 64; 300 mg, 0.76 mmol), DIPEA (0.396 mL,2.27 mmol) and AcOH (0.130 mL, 2.27 mmol) in DCM (10 mL) at 25° C. undernitrogen. After stirring at 25° C. for 0.5 hour, sodiumtriacetoxyborohydride (481 mg, 2.27 mmol) was added and the reactionstirred at 25° C. for 0.5 hour and heated at 50° C. for 12 hours. Thereaction mixture was quenched with saturated NaHCO₃ (20 mL) andextracted with DCM (2×75 mL). The organic phases ere dried over Na₂SO₄,filtered and evaporated to afford a yellow residue. The crude productwas purified by flash silica chromatography, elution gradient 3 to 4%MeOH in DCM. Pure fractions were evaporated to dryness to afford(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-((4-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 82; 240 mg, 76%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃, 20.5° C.) δ 1.37 (3H, d), 2.79 (3H, d), 4.10 (1H, dd), 4.25 (1H,tdd), 4.35-4.53 (2H, m), 5.50 (1H, d), 6.64 (1H, t), 7.33-7.47 (1H, m),7.61 (1H, s), 7.99 (1H, s), 8.44 (1H, d), 8.69 (1H, dd). m/z (ES+),[M+H]+=419.

Intermediate 83 4-(Difluoromethyl)picolinaldehyde

LiAlH₄ (0.274 g, 7.22 mmol) was added to4-(difluoromethyl)-N-methoxy-N-methylpicolinamide (Intermediate 84; 1.2g, 5.55 mmol) in THF (10 mL) cooled to −78° C. under nitrogen. Theresulting solution was stirred at −78° C. for 20 minutes. EtOAc (1 mL)was added, then the reaction quenched with water (0.3 mL) at −78° C. 15%NaOH aqueous solution (1.5 mL), further water (0.3 mL) was added and theresulting solids removed by filtration. The filtrate was dried overNa₂SO₄, filtered and evaporated to afford4-(difluoromethyl)picolinaldehyde (Intermediate 83; 1.09 g) as a greenoil. The product was used in the next step directly without furtherpurification. m/z (ES+), [M+H]+=158.

Intermediate 84 4-(Difluoromethyl)-N-methoxy-N-methylpicolinamide

Trimethylaluminum (2M in n-hexane, 40.1 mL, 80.15 mmol) was added toN,O-dimethylhydroxylamine hydrochloride (6.25 g, 64.12 mmol) in DCM (80mL) at 0° C. over a period of 20 minutes under nitrogen. The resultingsolution was stirred at 0° C. for 20 minutes. Methyl4-(difluoromethyl)picolinate (Intermediate 85; 3.0 g, 16.03 mmol) in DCM(20 mL) was added to reaction mixture at 0° C. and the resultingsolution was stirred at 0° C. for 2 hours. The reaction mixture wasquenched with 2M NaOH (50 mL) at 0° C. and extracted with DCM (3×100mL). The organic phases were dried over Na₂SO₄, filtered and evaporatedto afford yellow oil. The crude product was purified by flash silicachromatography, elution gradient 30 to 40% EtOAc in petroleum ether.Pure fractions were evaporated to dryness to afford4-(difluoromethyl)-N-methoxy-N-methylpicolinamide (Intermediate 84; 2.47g, 71.3%) as a yellow oil. ¹H NMR (400 MHz, MeOD, 20.3° C.) δ 3.42 (3H,s), 3.73 (3H, s), 6.94 (1H, t), 7.65-7.72 (1H, m), 8.75-8.82 (1H, m).m/z (ES+), [M+H]+=217.

Intermediate 85 Methyl 4-(difluoromethyl)picolinate

2-Chloro-4-(difluoromethyl)pyridine (Intermediate 86; 6.9 g, 42.19mmol), potassium acetate (8.28 g, 84.38 mmol) and Pd(dppf)Cl₂ (1.543 g,2.11 mmol) in MeOH (150 mL) were stirred under an atmosphere of CO at 10atm at 70° C. for 24 hours. The mixture was then filtered and thefiltrate was evaporated under reduced pressure. The crude product waspurified by flash silica chromatography, elution gradient 20 to 30%EtOAc in petroleum ether. Pure fractions were evaporated to dryness toafford methyl 4-(difluoromethyl)picolinate (Intermediate 85; 6.30 g,80%) as a yellow oil. ¹H NMR (400 MHz, MeOD, 20.1° C.) δ 4.03 (3H, s),6.98 (1H, t), 7.79-7.86 (1H, m), 8.30 (1H, dd), 8.86 (1H, dd). m/z(ES+), [M+H]+=188.

Intermediate 86 2-Chloro-4-(difluoromethyl)pyridine

DAST (20.53 mL, 155.42 mmol) was added dropwise to2-chloroisonicotinaldehyde (10 g, 70.64 mmol) in DCM (150 mL) at 0° C.over a period of 10 minutes under nitrogen. The temperature wasincreased to room temperature and stirred for 12 hours. The reactionmixture was quenched and adjusted to pH 7-8 with saturated NaHCO₃ at 0°C. The aqueous phase was extracted with DCM (3×150 mL), the organicphases dried over Na₂SO₄, filtered and evaporated to afford yellow oil.The crude product was purified by flash silica chromatography, elutiongradient 5 to 10% EtOAc in petroleum ether. Pure fractions wereevaporated to dryness to afford 2-chloro-4-(difluoromethyl)pyridine(Intermediate 86; 7.00 g, 60.6%) as a yellow oil. ¹H NMR (400 MHz,CDCl₃, 20.5° C.) δ 6.65 (1H, t), 7.38 (1H, dd), 7.49 (1H, s), 8.55 (1H,dd). m/z (ES+), [M+H]+=164.

Example 32(S)-6-Methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

3rd Generation BrettPhos precatalyst (12.42 mg, 0.01 mmol) was added to(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-7-((6-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 87; 120 mg, 0.27 mmol), 1-methyl-1H-pyrazol-5-amine (66.5mg, 0.69 mmol) and Cs₂CO₃ (179 mg, 0.55 mmol) in 1,4-dioxane (4 mL) at25° C. under nitrogen. The resulting mixture was stirred at 100° C. for8 hours. The solvent was then removed under reduced pressure. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 6% MeOH in DCM. Pure fractions were evaporated to dryness to afford ayellow residue. This residue was purified further by preparative HPLC(XSelect CSH Prep C18 OBD column, 5 silica, 19 mm diameter, 150 mmlength), using decreasingly polar mixtures of water (containing 0.03%NH₃) and MeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford(S)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 32; 60 mg, 43.9%) as a white solid. ¹H NMR (300 MHz, DMSO) δ1.25 (d, 3H), 3.71 (s, 3H), 4.14-4.21 (m, 1H), 4.34-4.46 (m, 1H),4.56-4.71 (m, 2H), 5.27 (d, 1H), 6.32 (d, 1H), 7.35 (d, 1H), 7.98 (s,1H), 8.13 (d, 1H), 8.34 (s, 1H), 9.24 (s, 1H), 9.41 (s, 1H). m/z (ES+),[M+H]+=499.

Intermediate 87(S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-6-methyl-7-((6-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

Sodium acetate (212 mg, 2.58 mmol) was added to (S)-ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-(2-(((6-(trifluoromethyl)pyrimidin-4-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate(Intermediate 88; 250 mg, 0.52 mmol) in EtOH (5 mL) and the resultingmixture was stirred at 80° C. for 20 hours. The solvent was then removedunder reduced pressure. The crude product was purified by flash silicachromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractionswere evaporated to dryness to afford(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-7-((6-(trifluoromethyl)pyrimidin-4-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 87; 120 mg, 53.1%) as a pale yellow solid. ¹H NMR (300MHz, CDCl₃, 20.5° C.) δ 1.45 (d, 3H), 2.79 (s, 3H), 4.43 (d, 1H),4.15-4.25 (m 1H), 4.60 (dd, 1H), 5.50 (d, 1H), 7.82 (d, 1H), 8.03 (s,1H), 8.46 (s, 1H), 9.34 (s, 1H). m/z (ES+), [M+H]+=438.

Intermediate 88 (S)-Ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-(2-(((6-(trifluoromethyl)pyrimidin-4-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate

Cp₂ZrHCl (492 mg, 1.91 mmol) was added toN-methoxy-N-methyl-6-(trifluoromethyl)pyrimidine-4-carboxamide(Intermediate 89; 300 mg, 1.28 mmol) in THF (10 mL) under nitrogen. Theresulting mixture was stirred at 25° C. for 20 minutes and then useddirectly. Sodium triacetoxyborohydride (385 mg, 1.81 mmol), acetic acid(0.104 mL, 1.81 mmol), (S)-ethyl1-(2-aminopropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 64; 240 mg, 0.60 mmol) and DIPEA (0.317mL, 1.81 mmol) in DCM (15 mL) were added and the resulting mixture wasstirred at 25° C. for 1 hour. Further sodium triacetoxyborohydride (385mg, 1.81 mmol) was added and stirred for a further 1 hour. The reactionmixture was then poured into saturated NaHCO₃ (75 mL) and extracted withDCM (3×25 mL). The organic phases were dried over Na₂SO₄, filtered andevaporated. The crude product was purified by flash silicachromatography, elution gradient 0 to 5% DCM in MeOH. Pure fractionswere evaporated to dryness to afford (S)-ethyl4-(2-chloro-5-methylpyrimidin-4-yl)-1-(2-(((6-(trifluoromethyl)pyrimidin-4-yl)methyl)amino)propyl)-1H-imidazole-2-carboxylate(Intermediate 88; 250 mg, 85%) as a pale yellow solid. m/z (ES+),[M+H]+=484.

Intermediate 89N-Methoxy-N-methyl-6-(trifluoromethyl)pyrimidine-4-carboxamide

Trimethylaluminum (2M in n-hexane, 72.8 mL, 145.54 mmol) was addeddropwise to N,O-dimethylhydroxylamine hydrochloride (10.65 g, 109.16mmol) in DCM (150 mL) at 0° C. over a period of 20 minutes undernitrogen. The resulting solution was stirred at 0° C. for 20 minutes.Methyl 6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 90; 7.5g, 36.39 mmol) in DCM (70 mL) was added dropwise to reaction mixture at0° C. The reaction mixture was then stirred for 1 hour at 0° C. Thereaction was quenched with 2M NaOH (100 mL) and extracted with DCM(3×150 mL). The organic phases were dried over Na₂SO₄, filtered andevaporated to afford yellow oil. The crude product was purified by flashsilica chromatography, elution gradient 0 to 25% EtOAc in petroleumether. Pure fractions were evaporated to dryness to affordN-methoxy-N-methyl-6-(trifluoromethyl)pyrimidine-4-carboxamide(Intermediate 89; 5.63 g, 65.8%) as a yellow oil. ¹H NMR (400 MHz,CDCl₃, 20.2° C.) δ 3.42 (3H, s), 3.79 (3H, s), 7.90 (1H, s), 9.41-9.47(1H, m). m/z (ES+), [M+H]+=236.

Intermediate 90 Methyl 6-(trifluoromethyl)pyrimidine-4-carboxylate

4-Chloro-6-(trifluoromethyl)pyrimidine (10 g, 54.79 mmol), potassiumacetate (10.75 g, 109.57 mmol) and Pd(dppf)Cl₂ (2.00 g, 2.74 mmol) inMeOH (300 mL) were stirred under an atmosphere of CO at 10 atm and 70°C. for 6 hours. The mixture was filtered and the filtrate was evaporatedunder reduced pressure. The crude product was purified by flash silicachromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Purefractions were evaporated to dryness to afford methyl6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 90; 7.86 g,69.6%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃, 20.3° C.) δ 4.11 (3H,s), 8.37 (1H, d), 9.55-9.61 (1H, m). m/z (ES+), [M+H]+=207.

Example 337-(3,4-Difluorobenzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

2nd Generation XantPhos precatalyst (78 mg, 0.09 mmol) was added to2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 91; 340 mg, 0.87 mmol), 1-methyl-1H-pyrazol-5-amine (169mg, 1.74 mmol) and Cs₂CO₃ (568 mg, 1.74 mmol) in 1,4-dioxane (5 mL) at25° C. under nitrogen. The resulting solution was stirred at 100° C. for12 hours. The solvent was then removed by distillation under vacuum. Thecrude product was purified by flash silica chromatography, elutiongradient 3 to 5% MeOH in DCM. Pure fractions were evaporated to drynessto afford a solid. This solid was purified further by preparative HPLC(XSelect CSH Prep C18 OBD column, 5μ silica, 19 mm diameter, 150 mmlength), using decreasingly polar mixtures of water (containing 0.05%NH₄HCO₃) and MeCN as eluents. Fractions containing the desired compoundwere evaporated to dryness to afford7-(3,4-difluorobenzyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 33; 89 mg, 22.6%) as a white solid. ¹H NMR (400 MHz, CDCl₃,20.1° C.) δ 2.68 (3H, d), 3.68-3.76 (2H, m), 3.80 (3H, s), 4.25-4.33(2H, m), 4.77 (2H, s), 6.29 (1H, d), 6.90 (1H, s), 7.07-7.28 (3H, m),7.49 (1H, d), 7.69 (1H, s), 8.29 (1H, d). m/z (ES+), [M+H]+=451.

Intermediate 912-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

NaH (91 mg, 2.28 mmol) was added to2-(2-chloro-5-methylpyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 48; 200 mg, 0.76 mmol) in DMF (5 mL) at 25° C. undernitrogen. The resulting solution was stirred at 25° C. for 30 minutes.4-(bromomethyl)-1,2-difluorobenzene (314 mg, 1.52 mmol) was added andthe resulting solution was stirred at 25° C. for 12 hours. The reactionmixture was poured into water (50 mL), the precipitate was collected byfiltration, washed with water (50 mL) and dried under vacuum to afford2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 91; 340 mg) as a yellow solid, which was used directlywith further purification. ¹H NMR (400 MHz, DMSO, 19.9° C.) δ 2.64 (3H,s), 3.74-3.82 (2H, m), 4.36-4.44 (2H, m), 4.70 (2H, s), 7.37-7.51 (3H,m), 8.26 (1H, s), 8.61 (1H, s). m/z (ES+), [M+H]+=390.

Example 34 Preparation of(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one adipic acid adduct, Form 1

50 mg of(R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 18) was dissolved in approximately 0.5 mL of methanol. A heatgun was used to aid dissolution. 16 mg of adipic acid was dissolved inapproximately 0.5 ml of methanol. A heat gun was used to aiddissolution. The(R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-onesolution was then slowly added to the adipic acid solution. Thisremained as a solution. A magnetic stirrer bar was added and thesolution allowed to stir at ambient temperature. A precipitate was seenafter approximately 15 minutes. Further volumes of methanol were addeduntil a free flowing precipitate was achieved and the precipitate wasallowed to stir overnight. The precipitate was then filtered to afford(R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneadipic acid adduct (Example 34), Form 1, in a 1:2 molar ratio of adipicacid:(R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneas determined by ¹H NMR. ¹H NMR (500 MHz, Methanol-d₄, 27° C.) δ 8.24(1H, s), 7.82 (1H, s), 7.41 (1H, d), 7.35 (1H, ddd), 7.28-7.20 (3H, m),6.31 (1H, d), 5.18 (1H, d), 4.52-4.39 (3H, m), 4.03-4.00 (1H, m), 3.73(3H, s), 3.46-3.43 (1H, m), 3.39-3.35 (1H, m), 3.23 (3H, s), 2.53 (3H,s), 2.30 (2H, m), 1.63 (2H, m), exchangeable carboxylic acid protons notobserved. The sample was analysed by XRPD (see FIG. 3) and DSC (see FIG.4).(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneadipic acid adduct Form 1 was determined to be crystalline by XRPD andhad a melting point of 185.4° C. (onset).

Example 35 Preparation of the Ethanesulfonic acid adduct of(S)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 35a; 2.2 g, 5.07 mmol), 1-methyl-1H-pyrazol-5-amine (0.754g, 7.61 mmol) and cesium carbonate (3.30 g, 10.14 mmol) were dissolvedin 2-MeTHF (25 mL) and water (2.5 mL) and degassed with nitrogen.2′-(dicyclohexylphosphanyl)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (0.160g, 0.41 mmol) and Pd₂dba₃ (0.186 g, 0.20 mmol) were added and themixture further degassed with nitrogen. The reaction was then heated at80° C. for 24 hours. The reaction was cooled to ambient temperature andfurther 2′-(dicyclohexylphosphanyl)-N,N-dimethyl-[1,1′-biphenyl]-2-amine(0.160 g, 0.41 mmol) and Pd₂dba₃ (0.186 g, 0.20 mmol) were added and thereaction degassed with nitrogen. The reaction was then stirred at 80° C.for 16 hours. Silicycle (1.2 g, SiliaMetS Thiol) was added and thereaction cooled to ambient temperature. The reaction mixture wasfiltered through celite washing with EtOAc. The reaction was extractedwith ethyl acetate, washed with aqueous citric acid (0.5 M) andsaturated sodium bicarbonate. The volatiles were then removed underreduced pressure. Purification by preparative supercritical fluidchromatography (Kromasil DIOL column, 250 mm×50 mm, 10 μm, mobile phase25% EtOH/NH₃ 100/0.5 in CO₂, 140 bar) afforded(S)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(1.38 g) which was used without further purification in the next stage.(S)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(1.3 g, 1.93 mmol) from the previous step was dissolved in acetonitrile(2 mL) and heated to 66° C. Ethanesulfonic acid (0.22 mL, 2.63 mmol) inacetonitrile (2 mL) was then added. The reaction was then stirred atambient temperature for 1 hour. A precipitate was observed. Furtheracetonitrile (3 mL) was added and the precipitate filtered, washed withacetonitrile (3 mL) and dried under vacuum for 66 hours to afford theethanesulfonic adduct of(S)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(0.41 g). The filtrate was evaporated under reduced pressure andacetonitrile (3 mL) and MTBE (2 mL) were added. The resultingprecipitate was filtered and dried under vacuum to afford furtherethanesulfonic adduct of(S)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(0.73 g). The 2 batches were combined to afford the ethanesulfonic acidadduct of(S)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 35; 1.14 g, 72%) in a 1:2 molar ratio of ethane sulfonicacid:(S)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneas determined by ¹H NMR. ¹H NMR (500 MHz, DMSO, 27° C.) 1.08 (1.5H, t),2.42 (1H, q), 2.52 (3H, m), 3.18 (3H, s), 3.32 (1H, dd), 3.41 (1H, dd),3.73 (3H, s), 4.05 (1H, dtd), 4.39 (1H, d), 4.43-4.56 (2H, m), 5.09 (1H,d), 6.38 (1H, d), 7.19-7.32 (1H, m), 7.38-7.45 (2H, m), 7.48 (1H, ddd),7.98 (1H, s), 8.36 (1H, d), 9.38 (1H, s). m/z (ES+) [M+H]+ 495.

Intermediate 35a(S)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 35b; 1.8 g, 5.85 mmol) and Cs₂CO₃ (2.67 g, 8.19 mmol) wereslurried in acetronitrile (20 mL) and heated to 70° C. under nitrogen.4-(bromomethyl)-1,2-difluorobenzene (1.48 g, 7.02 mmol) in acetonitrile(3 mL) was added via syringe to the slurry and the reaction was stirredat 70° C. for 23 hours. The volatiles were then removed under reducedpressure and ethyl acetate (30 mL) and then water (20 mL) was added tothe residue. The phases were separated the aqueous phase was extractedwith ethyl acetate (2×20 mL). The organic phases were combined and thevolatiles removed under reduced pressure. The resulting solid wassuspended in heptane/MTBE (4:1, 30 mL) and stirred at 50° C. for 2hours. The solid was filtered off and dried under reduced pressure toafford(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 35a; 2.36 g, 93%) as a solid. ¹H NMR (400 MHz, CDCl₃, 25°C.) δ 2.77 (3H, s), 3.28 (4H, s), 3.38 (1H, dd), 3.81 (1H, m), 4.22 (2H,m), 4.41 (1H, dd), 5.37 (1H, d), 7.10-7.26 (3H, m), 7.94 (1H, s), 8.42(1H, s). m/z (ES+), [M+H]+=434.

Intermediate 35b(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

Ethyl 4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylate(Intermediate 23; 2 g, 7.42 mmol) and K₂CO₃ (1.23 g, 8.91 mmol) weresuspended in 1,4-dioxane (20 mL) and acetone (20 mL). tert-Butyl(R)-4-(methoxymethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(Intermediate 35c; 2.18 g, 8.17 mmol) in acetone (15 mL) was added atambient temperature for 3 days. The mixture was filtered through celiteand the solids rinsed with acetone (15 mL). The filtrate was thenconcentrated to a total volume of (10 mL). A solution of HCl (5M inisopropanol, 10.39 mL) was added and the reaction stirred at ambienttemperature for 16 hours. Triethylamine (10.33 mL, 74.24 mmol) was addedslowly followed by isopropanol (15 mL) to afford a suspension. Thereaction was then heated at 50° C. for 3 hours. Water (40 mL) was addedwhich resulted in a fine suspension. The suspension was stirred at 50°C. for 30 minutes and then at ambient temperature for 16 hours. Theprecipitate was then filtered, and washed with 50% acetone in water(2×25 mL) and dried under reduced pressure at 40° C. for 4 days toafford(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 35b; 1.95 g, 85%) as a solid. ¹H NMR (400 MHz, DMSO, 20°C.) δ 2.61 (s, 3H), 3.26 (s, 3H), 3.33-3.45 (m, 2H), 3.99 (br s, 1H),4.30 (dd, 1H), 4.44 (dd, 1H), 8.26 (s, 1H), 8.42 (d, 1H), 8.58 (s, 1H).m/z (ES+), [M+H]+=308. Intermediate 35c is made in an analogous mannerto Intermediate 57 starting from (S)-tert-butyl(1-hydroxy-3-methoxypropan-2-yl)carbamate

Intermediate 35c tert-Butyl(R)-4-(methoxymethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

¹H NMR (400 MHz, MeOD) δ 1.54 (s, 9H), 3.40 (s, 3H), 3.61 (d, 2H), 4.46(qd, 1H), 4.60 (dd, 1H), 4.68 (dd, 1H). m/z: ES+ [M+H]+ 268.

Example 36(R)-6-Methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

(R)-2-(2-Chloro-5-methylpyrimidin-4-yl)-6-methyl-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 91; 187 mg, 0.43 mmol), 1-methyl-1H-pyrazol-5-amine (104mg, 1.07 mmol), Cs₂CO₃ (279 mg, 0.86 mmol) and 2nd Generation XantPhosprecatalyst (38.0 mg, 0.04 mmol) in 1,4-dioxane (5 mL) was stirred underan atmosphere of nitrogen at 110° C. for 16 hours. The solvent wasremoved by distillation under vacuum. The crude product was purified byflash silica chromatography, elution gradient 3 to 5% MeOH in DCM. Theproduct was further purified by preparative HPLC (XSelect CSH Prep C18OBD column, 5 silica, 19 mm diameter, 150 mm length), using decreasinglypolar mixtures of water (containing 0.01% NH₄HCO₃) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness toafford(R)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(112 mg, 52.6%) as a white solid. ¹H NMR (400 MHz, DMSO, 20.9° C.) δ1.22 (3H, d), 2.52 (3H, s), 3.35 (1H, s), 3.71 (3H, s), 4.13 (1H, ddd),4.40 (1H, dd), 4.51-4.63 (2H, m), 5.22 (1H, d), 6.31 (1H, d), 7.34 (1H,d), 7.78 (1H, d), 7.84 (1H, d), 7.97 (1H, s), 8.10 (1H, t), 8.33 (1H,d), 9.24 (1H, s). m/z (ES+), [M+H]+=498.

Intermediate 92(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

6-(Trifluoromethyl)picolinaldehyde (126 mg, 0.72 mmol) was added to(R)-ethyl1-(2-aminopropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 93; 260 mg, 0.66 mmol), DIPEA (0.343 mL,1.97 mmol) and AcOH (0.113 mL, 1.97 mmol) in DCM (10 mL) at 25° C. undernitrogen. The resulting solution was stirred at 25° C. for 20 minutes.Sodium triacetoxyborohydride (417 mg, 1.97 mmol) was added to thereaction mixture and the resulting solution was stirred at 25° C. for 1hour and then at 50° C. for 12 hours. The reaction mixture was pouredinto water (10 mL), extracted with DCM (3×15 mL), the organic layer wasdried over Na₂SO₄, filtered and evaporated to afford a yellow oil. Thecrude product was purified by flash silica chromatography, elutiongradient 3 to 4% MeOH in DCM. Pure fractions were evaporated to drynessto afford(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 92; 187 mg, 65.3%) as a colourless oil. m/z (ES+),[M+H]+=437.

Intermediate 93 (R)-Ethyl1-(2-aminopropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride

Intermediate 93 was prepared in an analogous manner to Intermediate 65,using (R)-tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide. Intermediate 93 exhibited the following analytical data. ¹HNMR (400 MHz, DMSO, 22° C.) δ 1.27 (3H, d), 1.36 (3H, t), 2.64 (3H, s),3.57 (3H, s), 3.74 (1H, s), 4.33-4.44 (2H, m), 4.58-4.75 (2H, m), 8.33(3H, s), 8.47 (1H, s), 8.64 (1H, s). m/z (ES+), [M+H]+=324.

Example 37(R)-7-((6-(Difluoromethyl)pyridin-2-yl)methyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

3rd Generation BrettPhos precatalyst (60.6 mg, 0.07 mmol) was added to(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 94; 280 mg, 0.67 mmol), 1-methyl-1H-pyrazol-5-amine (162mg, 1.67 mmol) and Cs₂CO₃ (436 mg, 1.34 mmol) in 1,4-dioxane (10 mL) at25° C. under nitrogen. The resulting mixture was stirred at 100° C. for8 hours. The solvent was then removed under reduced pressure. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 6% MeOH in DCM. Pure fractions were evaporated to dryness to afford ayellow residue. The residue was further purified by preparative HPLC(XSelect CSH Prep C18 OBD column, 5μ silica, 19 mm diameter, 150 mmlength), using decreasingly polar mixtures of water (containing 0.03%NH₃) and MeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford(R)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 37; 119 mg, 37.1%) as a solid. ¹H NMR (400 MHz, DMSO, 20° C.) δ1.20 (3H, d), 2.51 (3H, s), 3.70 (3H, s), 4.10 (1H, d), 4.34-4.43 (1H,m), 4.47-4.61 (2H, m), 5.21 (1H, d), 6.30 (1H, d), 6.97 (1H, t), 7.34(1H, d), 7.59-7.66 (2H, m), 7.94-8.04 (2H, m), 8.33 (1H, s), 9.23 (1H,s). m/z (ES+) [M+H]+ 480.

Intermediate 94(R)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

6-(Difluoromethyl)picolinaldehyde (214 mg, 1.36 mmol) was added to(R)-ethyl1-(2-aminopropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-2-carboxylatedihydrochloride (Intermediate 93; 270 mg, 0.68 mmol), DIPEA (0.357 mL,2.04 mmol) and AcOH (0.117 mL, 2.04 mmol) in DCM (10 mL) at 25° C. undernitrogen. After stirring at 25° C. for 1 hour, sodiumtriacetoxyborohydride (433 mg, 2.04 mmol) was added and the resultingmixture was stirred at 25° C. for 1 hour and heated at 50° C. for 5hours. The reaction mixture was quenched with saturated NaHCO₃ (20 mL)and extracted with DCM (2×75 mL). The organic layer was dried overNa₂SO₄, filtered and evaporated to afford a yellow residue. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 94; 280 mg, 98%) as a yellow solid. ¹H NMR (400 MHz, DMSO,20° C.) δ 1.21 (3H, d), 2.64 (3H, d), 4.09-4.16 (1H, m), 4.35 (1H, dd),4.49-4.64 (2H, m), 5.22 (1H, d), 6.82-7.12 (1H, m), 7.60-7.68 (2H, m),7.95-8.05 (1H, m), 8.30 (1H, s), 8.61 (1H, s). m/z (ES+) [M+H]+ 419.

Example 38(R)-7-(3-(Difluoromethyl)benzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

(R)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3-(difluoromethyl)benzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 95; 288 mg, 0.64 mmol), 1-methyl-1H-pyrazol-5-amine (68.7mg, 0.71 mmol), cesium carbonate (419 mg, 1.29 mmol) and BrettPhos 3rdgeneration pre-catalyst (29.1 mg, 0.03 mmol) were suspended intert-butanol (6 mL) and de-gassed for 10 minutes. The reaction washeated to 80° C. for 18 hours under nitrogen. The reaction was thendiluted with ethyl acetate (75 mL) and washed with saturated aqueoussodium bicarbonate (25 mL), dried (sodium sulfate) and concentrated invacuo to give a brown gum. The crude product was purified by preparativeHPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100mm length), using decreasingly polar mixtures of water (containing 1%NH₃) and MeCN as eluents. Fractions containing the desired compound wereevaporated to dryness afford(R)-7-(3-(difluoromethyl)benzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 38; 88 mg, 26.9%) as a white solid. ¹H NMR (500 MHz, DMSO, 30°C.) 2.53 (2H, s), 3.19 (1H, d), 3.33 (3H, d), 3.40 (1H, dd), 3.71 (3H,d), 4.03 (1H, q), 4.09 (1H, q), 4.4-4.57 (3H, m), 5.17 (1H, d), 6.31(1H, d), 7.05 (1H, t), 7.34 (1H, d), 7.5-7.56 (2H, m), 7.56-7.63 (2H,m), 7.95 (1H, s), 8.33 (1H, s), 9.20 (1H, s). m/z ES+ [M+H]+ 509.

Intermediate 95(R)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3-(difluoromethyl)benzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

Sodium hydride (60% dispersion) (28.6 mg, 0.71 mmol) was added to(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 61; 200 mg, 0.65 mmol) in DMF (15 mL) under nitrogen. Theresulting suspension was stirred at 20° C. for 30 minutes.1-(Chloromethyl)-3-(difluoromethyl)benzene (126 mg, 0.71 mmol) was addedfollowed by tetrabutylammonium iodide (24.01 mg, 0.06 mmol) and theresulting solution stirred at 20° C. for 18 hours. It was diluted withsaturated aqueous ammonium chloride (30 mL) and extracted with ethylacetate (2×70 mL). The combined organics were dried (sodium sulfate) andconcentrated in vacuo to give(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3-(difluoromethyl)benzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 95; 321 mg, >100%) as a gum which was used in the nextstep without further purification. ¹H NMR (400 MHz, DMSO, 30° C.) 2.64(3H, s), 3.17 (3H, s), 3.40 (2H, dd), 3.99-4.11 (1H, m), 4.4-4.59 (3H,m), 5.15 (1H, d), 7.03 (1H, t), 7.5-7.53 (2H, m), 7.59 (1H, d), 7.96(1H, s), 8.25 (1H, s), 8.59 (1H, s). m/z ES+ [M+H]+ 448.

Example 39(R)-6-(Methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

(R)-2-(2-Chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 96; 201 mg, 0.43 mmol), 1-methyl-1H-pyrazol-5-amine (46.0mg, 0.47 mmol), cesium carbonate (281 mg, 0.86 mmol) and BrettPhos 3rdgeneration pre-catalyst (19.51 mg, 0.02 mmol) were suspended intert-butanol (5 mL) and de-gassed for 10 minutes. The reaction washeated to 80° C. for 18 hours under nitrogen. The reaction was thendiluted with ethyl acetate (75 mL) and washed with saturated aqueoussodium bicarbonate (25 mL), dried (sodium sulfate) and concentrated invacuo to give a brown gum. The crude product was purified by preparativeHPLC (Waters XBridge Prep C18 OBD column, 5 silica, 30 mm diameter, 100mm length), using decreasingly polar mixtures of water (containing 1%NH₃) and MeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford(R)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 39; 68 mg, 29.9%) as a solid. ¹H NMR (500 MHz, DMSO, 30° C.)3.18 (1H, d), 3.20 (3H, d), 3.32 (3H, s), 3.39 (1H, dd), 3.54 (1H, dd),3.71 (3H, d), 4.51-4.63 (2H, m), 4.66 (1H, d), 5.24 (1H, d), 6.31 (1H,d), 7.34 (1H, dd), 7.78 (1H, d), 7.83 (1H, d), 7.98 (1H, s), 8.09 (1H,t), 8.33 (1H, s), 9.20 (1H, s). m/z ES+ [M+H]+ 528.

Intermediate 96(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

Sodium hydride (60% dispersion) (19.16 mg, 0.48 mmol) was added to(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 61; 134 mg, 0.44 mmol) in DMF (10 mL) under nitrogen. Theresulting suspension was stirred at 20° C. for 30 minutes.2-(Bromomethyl)-6-(trifluoromethyl)pyridine (115 mg, 0.48 mmol) wasadded and the resulting solution stirred at 20° C. for 18 hours. Thereaction was quenched with saturated aqueous ammonium chloride (30 mL)and extracted with ethyl acetate (2×70 mL). The combined organics weredried (sodium sulfate) and concentrated in vacuo to give(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 96; 203 mg, 100%) as a gum. ¹H NMR (400 MHz, DMSO, 30° C.)2.63 (3H, s), 3.20 (3H, s), 3.37-3.42 (1H, m), 3.54 (1H, dd), 4.20 (1H,dt), 4.56 (2H, d), 4.67 (1H, d), 5.23 (1H, d), 7.80 (2H, dd), 8.09 (1H,t), 8.29 (1H, s), 8.59 (1H, d). m/z ES+ [M+H]+ 467.

Example 40(R)-7-(3,5-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

(R)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3,5-difluorobenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 97; 280 mg, 0.65 mmol), 1-methyl-1H-pyrazol-5-amine (68.9mg, 0.71 mmol), cesium carbonate (421 mg, 1.29 mmol) and BrettPhos 3rdgeneration pre-catalyst (29.3 mg, 0.03 mmol) were suspended intert-butanol (6 mL) and de-gassed for 10 minutes. The reaction washeated to 80° C. for 18 hours under nitrogen. The reaction mixture wasdiluted with ethyl acetate (75 mL) and washed with saturated aqueoussodium bicarbonate (25 mL), dried (sodium sulfate) and concentrated invacuo to give a brown gum. The crude product was purified by preparativeHPLC (Waters XBridge Prep C18 OBD column, 5 silica, 30 mm diameter, 100mm length), using decreasingly polar mixtures of water (containing 1%NH₃) and MeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford(R)-7-(3,5-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 40; 80 mg, 25.1%) as an off white solid. ¹H NMR (500 MHz, DMSO,30° C.) 2.52 (3H, s), 3.19 (1H, s), 3.19 (3H, s), 3.35 (1H, dd), 3.43(1H, dd), 3.71 (3H, s), 4.43 (1H, d), 4.48-4.57 (2H, m), 5.12 (1H, d),6.30 (1H, d), 7.15 (3H, td), 7.34 (1H, d), 7.94 (1H, s), 8.32 (1H, s),9.18 (1H, s). m/z ES+ [M+H]+ 495.

Intermediate 97 was made in an analagous manner to Intermediate 96,using Intermediate 61 and 1-(bromomethyl)-3,5-difluorobenzene.

Intermediate 97(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,5-difluorobenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

¹H NMR (400 MHz, DMSO, 30° C.) 2.64 (3H, s), 3.18 (3H, s), 3.44 (2H,dd), 4.08 (1H, dd), 4.4-4.59 (3H, m), 5.10 (1H, d), 7.13 (3H, dt), 8.25(1H, s), 8.56-8.62 (1H, m). m/z ES+ [M+H]+ 434.

Example 41(R)-7-(3-Methoxybenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

(R)-2-(2-Chloro-5-methylpyrimidin-4-yl)-7-(3-methoxybenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Intermediate 98; 164 mg, 0.38 mmol), 1-methyl-1H-pyrazol-5-amine (40.9mg, 0.42 mmol), cesium carbonate (250 mg, 0.77 mmol) and BrettPhos 3rdgeneration pre-catalyst (17.37 mg, 0.02 mmol) were suspended intert-butanol (5 mL) and de-gassed for 10 minutes. The reaction washeated to 80° C. for 18 hours under nitrogen. The reaction was dilutedwith ethyl acetate (75 mL) and washed with saturated aqueous sodiumbicarbonate (25 mL), dried (sodium sulfate) and concentrated in vacuo togive a brown gum. The crude product was purified by preparative HPLC(Waters XBridge Prep C18 OBD column, 5 silica, 30 mm diameter, 100 mmlength), using decreasingly polar mixtures of water (containing 1% NH₃)and MeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford(R)-7-(3-methoxybenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one(Example 41; 58.0 mg, 31%) as an off white solid. ¹H NMR (500 MHz, DMSO,30° C.) 2.53 (3H, s), 3.18 (3H, d), 3.19 (1H, d), 3.38 (1H, dd), 3.70(3H, s), 3.76 (3H, s), 3.95-4.02 (1H, m), 4.33-4.43 (2H, m), 4.49-4.55(1H, m), 5.12 (1H, d), 6.30 (1H, d), 6.88 (1H, dd), 6.98 (2H, s),7.27-7.31 (1H, m), 7.34 (1H, d), 7.93 (1H, s), 8.29-8.36 (1H, m), 9.18(1H, s). m/z ES+[M+H]+ 489.

Intermediate 98 was made in an analagous manner to Intermediate 96,using Intermediate 61 and 1-(bromomethyl)-3-methoxybenzene.

Intermediate 98(R)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3-methoxybenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

¹H NMR (400 MHz, DMSO, 30° C.) 2.64 (3H, s), 3.17 (3H, s), 3.37-3.42(2H, m), 3.76 (3H, s), 3.98 (1H, s), 4.33-4.45 (2H, m), 4.49 (1H, d),5.04-5.19 (1H, m), 6.88 (1H, d), 6.97 (2H, d), 7.29 (1H, t), 8.24 (1H,s), 8.60 (1H, s). m/z ES+ [M+H]+ 428.

1. A compound of the Formula (I) or a pharmaceutically-acceptable adductthereof

wherein: R¹ is hydrogen, C₁₋₃ alkyl or —CH₂OMe; R² is pyridinyl,optionally substituted on 1 ring carbon atom by a substituentindependently selected from the group consisting of C₁₋₃ alkyl,difluoromethyl and trifluoromethyl; or R² is pyrimidinyl, optionallysubstituted on 1 ring carbon atom by a substituent independentlyselected from the group consisting of C₁₋₃ alkyl, difluoromethyl andtrifluoromethyl; or R² is phenyl optionally substituted on 1 or 2 ringcarbon atoms by a substituent independently selected from the groupconsisting of halo, difluoromethyl, trifluoromethyl, methoxy and —OCHF₂;and R³ is hydrogen, C₁₋₃ alkyl or chloro.
 2. A compound of formula (I)or a pharmaceutically-acceptable adduct thereof, as claimed in claim 1,wherein: R¹ is hydrogen, methyl or —CH₂OMe; R² is pyridinyl, optionallysubstituted on 1 ring carbon atom by a substituent independentlyselected from the group consisting of methyl, difluoromethyl andtrifluoromethyl; or R² is pyrimidinyl, optionally substituted on 1 ringcarbon atom by a substituent independently selected from the groupconsisting of methyl, difluoromethyl and trifluoromethyl; or R² isphenyl optionally substituted on 1 or 2 ring carbon atoms by asubstituent independently selected from the group consisting of fluoro,chloro, difluoromethyl, trifluoromethyl, methoxy and —OCHF₂; and R³ ishydrogen, methyl or chloro.
 3. A compound of formula (I) or apharmaceutically-acceptable adduct thereof, as claimed in claim 1,wherein: R¹ is hydrogen, methyl or —CH₂OMe; R² is pyridinyl, optionallysubstituted on 1 ring carbon atom by a substituent independentlyselected from the group consisting of methyl, difluoromethyl andtrifluoromethyl; or R² is pyrimidinyl, optionally substituted on 1 ringcarbon atom by a trifluoromethyl; or R² is phenyl optionally substitutedon 1 or 2 ring carbon atoms by a substituent independently selected fromthe group consisting of fluoro, chloro, difluoromethyl and methoxy; andR³ is hydrogen, methyl or chloro.
 4. A compound as claimed in claim 1,or a pharmaceutically-acceptable adduct thereof, wherein R² is6-(difluoromethyl)pyridin-2-yl, 3-chlorophenyl, 3,4-difluorophenyl or3,5-difluorophenyl.
 5. A compound as claimed in claim 1, or apharmaceutically-acceptable adduct thereof, wherein R² is6-(difluoromethyl)pyridin-2-yl.
 6. A compound as claimed in claim 1, ora pharmaceutically-acceptable adduct thereof, wherein R² is3-chlorophenyl.
 7. A compound as claimed in claim 1, or apharmaceutically-acceptable adduct thereof, wherein R² is3,4-difluorophenyl.
 8. A compound as claimed in claim 1, or apharmaceutically-acceptable adduct thereof, wherein R² is3,5-difluorophenyl.
 9. (canceled)
 10. A compound as claimed in claim 1,or a pharmaceutically-acceptable adduct thereof, wherein said compoundis;(S)-7-(3-chlorobenzyl)-6-methyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;(S)-7-((6-(difluoromethyl)pyridin-2-yl)methyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one;(R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one; or(S)-7-(3,5-difluorobenzyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one.11. A compound as claimed in claim 1, or a pharmaceutically-acceptableadduct thereof, wherein said compound is(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one.12. A pharmaceutically-acceptable adduct of a compound of formula (I) asclaimed in claim 1, which is(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct.
 13. A crystalline form of(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneEthanesulfonic acid adduct as claimed in claim
 12. 14. Apharmaceutically-acceptable adduct of a compound of formula (I) asclaimed in claim 1, which is(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct.
 15. A crystalline form of(R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-oneAdipic acid adduct as claimed in claim
 14. 16.-18. (canceled)
 19. Amethod for the prevention or treatment of cancer in a warm bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound of theFormula (I) or a pharmaceutically-acceptable adduct thereof, as claimedin claim
 1. 20. A pharmaceutical composition comprising a compound ofFormula (I) or a pharmaceutically-acceptable adduct thereof, as claimedin claim 1, and a pharmaceutically-acceptable diluent or carrier.
 21. Acombination suitable for use in the treatment of cancer comprising acompound of Formula (I) or a pharmaceutically-acceptable adduct thereof,as claimed in claim 1, and another anti-tumour agent.
 22. A combinationas claimed in claim 21 comprising a compound of Formula (I) or apharmaceutically-acceptable adduct thereof, as claimed in claim 1, and aMEK inhibitor.
 23. A process for preparing a compound of formula (VI),said process comprising: a) reaction of a compound of formula (VIII)with a compound of formula (XVI) in the presence of a suitable base in asuitable solvent, under conditions of ambient or elevated temperatures;

wherein R¹ and R³ are defined for compound of formula (I) hereinbefore;L¹ is a leaving group or a pre-cursor to a leaving group; P³ is aprotecting group; and R⁴ is an alkyl group; and b) optionally, anintermediate sulfamic acid is removed under conditions of aqueous acidin a suitable solvent; and c) removal of the protecting group P³ in thepresence of a suitable acid in a suitable solvent, under ambienttemperatures.